Genetic Resistance to Prion Diseases

Yalçın Yaman; Cemal Ün

doi:10.5772/66916

Abstract

Prions are abnormal isoforms of the host‐encoded cellular prion proteins which are misfolding in its three‐dimensional structure acquire pathogenicity. Prions cause transmissible spongiform encephalopathy (TSEs) in humans and some animal species including sheep, goats, cattle, cat, deer and elk. TSEs, also called “prion diseases,” cause irreversible neurodegeneration in the central nervous system and are always fatal. Cellular prion proteins are encoded by prion protein gene (PRNP) in mammals; moreover, it is known that the variations in the PRNP gene have influence on the resistance and/or incubation period of the TSEs. It is well‐documented that after exposure to the pathogenic prions, development of some TSEs depend on the host PRNP genotype, for example, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, Creutzfeldt‐Jakob disease (CJD) and kuru in humans, as well. In this chapter, genetic resistance to prion diseases will be reviewed.

Keywords

TSE
prion disease
PRNP
genetic resistance

Author Information

Show +

Yalçın Yaman
- Department of Biometry and Genetics, Sheep Research Institute, Bandirma, Balıkesir, Turkey
Cemal Ün*
- Department of Biology, Faculty of Science, Ege University, İzmir, Turkey

*Address all correspondence to: cemaluen@gmail.com

1. Introduction

It is known that conformational changes in prion protein cause Creutzfeldt‐Jakob disease (CJD) in humans, scrapie disease in sheep and goats [1, 2], bovine spongiform encephalopathy (BSE) in cattle, feline spongiform encephalopathy in cat, and wasting disease in deer and elk.

Polymorphisms inside the prion protein‐coding gene (PRNP) in humans and also in some mammalian species have been appeared to impact disease susceptibility and pathologies [3]. In human population, kuru and CJD are profoundly related with polymorphism in codon 129. All CDJ affected individuals are known to be homozygous for methionine amino acid in codon 129 while at the same codon heterozygote individuals seem most resistant to kuru [4, 5]. Also, it is known that there is a high correlation between the polymorphisms in codons 136, 154, and 171 of the PRNP gene and the level of susceptibility to scrapie in sheep [3, 6, 7]. In cattle, numerous studies were carried out for discovering a relationship amongst BSE and polymorphisms in cattle genome [8–12]. The studies about BSE‐affected animals in Germany and USA represented the influence of PRNP promoter polymorphisms on BSE susceptibility in cattle [13, 14]. The impacts of insertion‐deletion (indel) polymorphisms within a location 1.6 kbp upstream of exon 1 and inside intron 1 (23‐bp and 12‐bp, respectively) on BSE susceptibility are determined by further analyses in cattle [15–17]. Despite the fact that cattle with the -/-23 bp promoter genotype and the –/12 bp intron 1 genotype have both been significantly connected with BSE, it could not be reached any consensus on which genotype is most identified with BSE [13, 15, 16, 18]. In addition, indel polymorphisms that affect the sensitivity of classical BSE appear not to be pertinent to other transmissible spongiform encephalopathies in cattle [19]. Until now, the incidence of PRNP gene promoter polymorphisms has been identified in some cattle in Asia [20, 21], Europe [13, 16, 18, 22] and America [14, 23].

2. Resistance in humans

There exist various types of human prion disease such as Creutzfeldt‐Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann Sträussler‐Scheinker syndrome (GSS). Related to the cause of the illness they exist in three main forms: Genetic, sporadic and acquired. Genetic form of the disease is caused by a mutation in prion protein‐coding gene (PRNP), whereas acquired form occurs by the transmission of disease from an animal or another human disease. The cause of sporadic form is not clear up to now [24–26].

The human prion‐coding gene consists of two exons and the second one contains the whole open reading frame. It is known that a valine amino acid at position 129 of the human prion protein provide resistancy to the Creutzfeldt‐Jakob disease. Both Valin129Valin and Methionine129Methionine genotypes are resistant to the disease, whereas Methionine129Methionine genotypes are susceptible [27, 28]. Another polymorphism at codon 219 was reported to be related with development of Creutzfeldt‐Jakob disease in Japanese population [29].

3. Resistance in small ruminants

Scrapie is a neurodegenerative disease of sheep and goats. As with other transmissible spongiform encephalopathies (TSE) which affect humans and animal species, scrapie is always fatal and characterized by long incubation periods ranging from months to years, vacuolation, neuronal loss and astrocytosis in the central nervous system (CNS) and has no inflammatory or immune responses [30]. The earliest reports of the scrapie based on middle of 1700s in Britain. Various terms such as “scrapie,” “scratchie,” “rubbers,” “rickets” and “goggles” were used to indicate the disease [31].

It is thought that scrapie first occurred in the United Kingdom in the eighteenth century and following decades, particularly after World War II, the disease spread by importation of the infected animals. Scrapie has reported nearly all over the world, for example, Iceland (1878), Canada (1938), USA (1947), Australia (1952), Norway (1958), India (1961), Republic of South Africa (1966), Kenya (1970), Germany (1973), Brazil (1978), Yemen (1979), Sweden (1988), Cyprus (1989) and Japan (1990), reviewed in reference [30].

Scrapie has been known for over 250 years; therefore, it is regarded to be prototype of the TSEs [30]. Earlier, researchers thought that it was a hereditary disease, but later, according to the results of the experimental transmission studies, they were considered that “Scrapie was a natural infection and gained from ground”. After seven years of working with several thousand breeding ewes within several hundred ewes were affected classical scrapie, H. B. Parry postulated some hypothesis that scrapie had a hereditary feature in a simple Mendelian autosomal recessive manner, development of the disease determined by genotype of the individuals, and it was not a natural infection. They observed that in high‐incidence flocks, many scrapie diseased individuals had affected parent or progeny [32, 33]. Later studies revealed the evidences that scrapie is a transmissible infection [34] which is caused by a kind of proteins called “prion” [35], and development and/or incubation period of the disease under genetic control [36–40].

3.1. Resistance in sheep

Sheep and goat prion protein‐coding gene (PRNP) which encodes the cellular prion protein located on chromosome 13 [41]. The gene structure of the sheep PRNP was determined by [40], they demonstrated that sheep PRNP encoded 256 amino acids and highly homologous with the PRNP gene of the other species. Furthermore, the authors suggest that arginine/glutamine substitution in the 171th position of the sheep PRNP might have affected the scrapie incubation period. According to the results of many subsequent study polymorphisms of 136th, 154th and 171th codons of ovine PRNP had a strong influence on susceptibility or resistance to the scrapie [8, 42–45].

Commonly encoded amino acids at three codons are as follows: alanine (A) or valine (V) at codon 136, arginine (R) or histidine (H) at codon 154 and glutamine (G), histidine (H) or arginine (R) at codon 171 and out of possible other combinations, common PRNP alleles are A136R154R171, A136R154Q171, A136R154H171, A136H154Q171 and V136R154Q171, (respectively, ARR, ARQ, ARH, AHQ and VRQ for short) [45, 46]. While ARR alleles related to resistance, VRQ is regarded as the most susceptible alleles. Until now, only three scrapie cases were reported in ARR homozygous sheep which are one case from Japan [47] and two cases from France and Germany [48]. Some studies on PrP genotype and their relevance to scrapie in scrapie diseased sheep are presented in Table 1.

Risk groups	PrP Genotypes	Norway n = 32 [49]	England n = 21 [50]	England n = 59 [51]	France n = 437 [52]	France n = 245 [53]	Ireland n = 154 [54]	Italy n = 34 [55]	The Netherlands n = 34 [45]	Iceland n = 101 [56]	Greece n = 216 [57]	Japan n = 15 [47]	Canada n = 249 [58]
1	ARR/ARR	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.066	0.000
2	ARR/AHQ	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.005	0.000	0.000
	ARR/ARH	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.014	0.000	0.000
	ARR/ARQ	0.063	0.000	0.000	0.005	0.008	0.000	0.000	0.000	0.000	0.120	0.066	0.000
3	ARQ/ARH	0.000	0.000	0.000	0.000	0.041	0.162	0.000	0.000	0.000	0.000	0.000	0.000
	ARQ/AHQ	0.000	0.000	0.017	0.016	0.004	0.000	0.059	0.000	0.000	0.176	0.000	0.004
	AHQ/AHQ	0.063	0.000	0.017	0.002	0.004	0.000	0.000	0.000	0.000	0.000	0.000	0.000
	ARH/ARH	0.000	0.000	0.000	0.000	0.004	0.006	0.000	0.000	0.000	0.005	0.000	0.000
	AHQ/ARH	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000
	ARQ/ARQ	0.031	0.143	0.136	0.210	0.371	0.422	0.941	0.088	0.465	0.509	0.867	0.916
4	ARR/VRQ	0.000	0.095	0.254	0.020	0.070	0.006	0.000	0.029	0.000	0.000	0.000	0.012
5	AHQ/VRQ	0.000	0.000	0.000	0.007	0.008	0.000	0.000	0.000	0.000	0.000	0.000	0.004
	ARH/VRQ	0.000	0.286	0.051	0.000	0.037	0.026	0.000	0.441	0.000	0.000	0.000	0.000
	ARQ/VRQ	0.156	0.476	0.407	0.470	0.371	0.363	0.000	0.353	0.406	0.000	0.000	0.052
	VRQ/VRQ	0.688	0.000	0.119	0.280	0.086	0.013	0.000	0.088	0.129	0.079	0.000	0.012

Table 1.

PrP genotype frequencies of the scrapie‐infected sheep in various countries.

There is no report about direct transmission from sheep to human in natural condition, nevertheless, scrapie can be transmitted interspecies by experimentally [59–61], furthermore, the cattle prion disease, Bovine spongiform encephalopathy (BSE) which is transmitted to human and causes a variant of Creutzfeldt‐Jakob disease (vCJD) [62], originated from the usage of scrapie contaminated material in cattle nutrition [63]. Even, in a more recent study, natural scrapie isolate was successfully transmitted to a primate (cynomolgus macaque) suggesting that scrapie has zoonotic potential to primates including human [64]. Epidemiological connection with scrapie, BSE and vCJD emerged public health concerns and lead to establishing scrapie eradication programs, including increasing the genetic resistance to scrapie in scrapie epidemic countries.

In 2001, Great Britain has established the “National Scrapie Plan” (NSP) intending to increase the frequencies of resistance alleles by selective breeding and eventually eradicate scrapie from British sheep herds. According to disease‐associated alleles, five risk groups were designated from R1 to R5 where is R1 referring at the lowest risk and R5 at highest risk [65]. NSP scrapie risk groups can be seen in Table 2.

Risk groups	Genotype of individuals	Degree of resistance/susceptibility
R1	ARR/ARR	Sheep that are most resistant to scrapie
R2	ARR/AHQ	Sheep that are resistant to scrapie, but will need careful selection when used further breeding
	ARR/ARH
	ARR/ARQ
R3	ARQ/ARH	Sheep that have little resistance and will need careful selection when used for further breeding
	ARQ/AHQ
	AHQ/AHQ
	ARH/ARH
	AHQ/ARH
	ARQ/ARQ
R4	ARR/VRQ	Sheep that are susceptible to scrapie and should not be used for breeding because of carrying VRQ allele
R5	AHQ/VRQ	Sheep that are highly susceptible to scrapie and should not be used for breeding
	ARH/VRQ
	ARQ/VRQ
	VRQ/VRQ

Table 2.

PrP genotypes and allocation of them into scrapie risk groups (adapted from reference [65]).

Reported case per year and estimated of the case number per million sheep according to risk groups in the United Kingdom (UK) are given in Table 3.

Risk groups	Case per year (n)	Percentage of sheep	Case per year per million (n)
R1	0	21.3	0
R2	2.3	35.7	0.7
R3	104.9	23.9	57.8
R4	12	9.6	6.3
R5	381.8	9.6	1175.6

Table 3.

Estimates of the number of reported cases of scrapie per million sheep of each risk groups in the UK (adapted from reference [46]).

European Union (EU) Commission has issued a regulation in 2003 that required the establish of a selective breeding program for resistance to TSE in each sheep breed of member states [66]; therefore, European member states have been implementing breeding programs based on elimination of the most susceptible alleles while increasing resistant allele frequencies. For example, as a result of intensive genetic selection programs, particularly in high genetic merit flocks, ARR allele frequencies increased from 50 to 69% in the UK, 49 to 85% in France, 38 to 70% in the Netherlands and 47 to 70% in Italy [67].

Given the importance of the disease, a lot of genotyping studies on sheep PRNP have carried out in the almost all over the world such as; in New Zealand and Australia [68], Brazil [69], Israel, Palestine, and Jordan [70], Turkey [71], Egypt and Saudi Arabia [72] and East Asia [73], whether scrapie have reported or never been reported.

3.2. Resistance in goats

First natural scrapie case in goats was defined in 1942 [74]. Although goat scrapie has rare incidence compared with sheep, a surveillance program between 2002 and 2009 was performed according to the EU commission direction and over 3000 scrapie cases were reported in goats [75]. Scrapie cases occurring in natural condition in goats have been reported, particularly throughout Europe [76–78]. Transmission of the scrapie from naturally affected sheep to goats which rearing together has often been observed [77, 79–81], in addition, transmission from goat to goat has been known [76].

In contrast to sheep, limited data are available related to scrapie resistance and PRNP alleles. Genotyping studies on goats PRNP have given various results in terms of disease susceptibility or resistance. Assessment of PRNP alleles in scrapie infected and non‐infected goats presented in Table 4.

Codons	AA substitution	Association to disease	References
18	W‐R		[82]
21	V‐A		[80]
23	L‐P		[80]
37	G‐V		[83, 84]
49	G‐S		[80]
101	Q‐R		[82]
110	T‐P		[83, 84]
127	G‐S	Incubation period/resistance	[85, 86]
133	L‐Q		[93]
137	M‐I		[93]
139	R‐S		[87]
142	I‐M	Incubation period	[84, 86, 88, 89]
142	I‐T		[84]
143	H‐R	Limited resistance	[80, 88]
145	G‐D		[87]
146	N‐S or D	Resistance	[78, 90]
151	R‐H		[78]
154	R‐H	Limited resistance	[78, 80, 83, 89]
168	P‐Q		[80]
194	T‐P		[84]
201	F‐L		[86]
208	R‐Q		[91]
211	R‐G		[85]
211	R‐Q	Lower susceptibility	[84, 89]
219	T‐I		[92]
220	Q‐H		[80]
222	Q‐K	Resistance	[83, 89, 90, 93]
232	G‐W		[82]
240	S‐P	Resistance (connected with codon 142)	[88, 89]

Table 4.

The PRNP polymorphisms of scrapie‐infected/noninfected goats and association of polymorphisms with scrapie resistance.

Abbreviations of the amino acids: A, alanine; D, aspartic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan.

As provided in Table 4, some relationships between caprine PRNP polymorphisms and scrapie resistance were defined. Encoding of serine instead of glycine at codon 127 has decreased the probability of clinical manifestation of the disease [86]. Isoleucine‐methionine dimorphism at codon 142 has found to be associated both experimental [88] and natural infection [86, 89]; furthermore, it is reported that [89] the presence of methionine‐isoleucine as heterozygous at codon 142 has been provided resistance only in proline‐proline homozygous animal at codon 240. Encoding of arginine at codon 143 has provided limited protection to natural scrapie [80]. While the presence of asparagine instead of Serine or Aspartic acid at codon 146 has been found to be related to susceptibility to natural infection [78], it also has reported that the presence of Serine as heterozygous at the same codon has associated with the extended incubation period in oral challenging [90]. According to the results of various studies, arginine‐histidine dimorphism at codon 154 has provided limited resistance [78, 80, 83, 89]. The presence of glutamine/arginine as heterozygous at codon 211 has been found to be related to lower susceptibility [89], and the presence of lysine at codon 222 has been associated with resistance to both natural [83, 89, 93] and oral [90] or intracerebral challenging [94].

Apart from these polymorphisms, an allele of caprine PRNP, which encodes shorter cellular prion protein, has been reported. An experimental transmission to a goat carrying this allele as heterozygote has died after an unusually long incubation period [95]. In addition, a novel 28 bp insertion in the promoter region of caprine PRNP was found by [96] in healthy Chinese native goat breeds. Although there is no information with respect to disease resistance, some associations between this insertion/deletion polymorphism and production trait were reported.

Influences of the remaining codons over scrapie resistance or susceptibility in goats are not known yet. Currently available data on genetic resistance to scrapie are considered insufficient to establish selective breeding programs in goats.

3.3. Atypical scrapie in sheep and goats

Norwegian researchers have recognized a novel type of scrapie case in 1998 which has unusual histopathological features comparing with classical scrapie. The geographical distribution of the disease indicated that it might be spontaneous scrapie, not a contagious disease. This atypical form of scrapie designated as Nor98 by the authors [97]. Later studies conducted on archived tissue specimens revealed that atypical scrapie is not a new disease and has been existed at least from late 1980s in the UK herds [98, 99]. In the following years, many atypical scrapie cases were reported in sheep and/or goats from [100–103], North America [104] and New Zealand [105], as well.

Atypical cases have appeared to relate with the PRNP genotypes considered relatively resistant to classical scrapie. Sheep which are carrier of AHQ allele have found to be more susceptible to atypical scrapie; moreover, unlike classical scrapie, it was demonstrated that the presence of phenylalanine at codon 141 strongly associated with atypical cases [51, 53, 100, 106–109]. Interestingly, according to results of case control studies, while VRQ allele which is the most classical scrapie have found to be related to low incidence in atypical scrapie [51, 53, 108], the most resistant ARR allele associated with higher incidence [53, 107, 109]. Distribution of PRNP genotypes and roles of codon 141 on atypical scrapie resistance demonstrated in Table 5.

Risk groups for classical scrapie	Genotype of individuals	n = 38 [106]	n = 69 [51]	n = 51 [109]	n = 248 [53]
R1	ARR/ARR		0.129	0.118	0.181
R2	ARR/AHQ	0.132	0.217	0.039	0.097
	ARR/ARH		0.014		0.012
	ARR/ARQ		0.029	0.039	0.040
	ARR/AFRQ	0.105	0.101	0.314	0.218
R3	ARQ/ARH
	AFRQ/ARH				0.004
	ARQ/AHQ	0.053	0.174	0.020	0.052
	AFRQ/AHQ	0.211	0.072		0.044
	AHQ/AHQ	0.211	0.145	0.039	0.024
	ARH/ARH			0.020	0.004
	AHQ/ARH	0.026		0.020	0.008
	ARQ/ARQ	0.053			0.008
	ARQ/AFRQ	0.079	0.014	0.176	0.173
	AFRQ/AFRQ	0.132	0.087	0.137	0.113
R4	ARR/VRQ
R5	AHQ/VRQ			0.020	0.004
	ARH/VRQ				0.004
	ARQ/VRQ
	AFRQ/VRQ		0.014	0.059	0.012
	VRQ/VRQ

Table 5.

PRNP genotypes according to codons 136, 154 and 171 (and codon 141 if the presence of phenylalanine residue) and association with atypical scrapie.

Although there is very limited data about relationship atypical scrapie and PRNP genotypes in goats, it has been reported that the presence of histidine at codon 154 may associated with atypical cases in goats, as well [103, 109].

European selective breeding programs against to classical scrapie in sheep already eliminating the AHQ and AFRQ alleles which have demonstrated to relate with atypical scrapie susceptibility; however, the major problem about ARR (resistant to classical scrapie but susceptible to atypical scrapie) and VRQ (susceptible to classical scrapie but resistant to atypical scrapie) alleles remains to be solved.

4. Resistance in cattle

Bovine spongiform encephalopathy (BSE), the cattle prion disease, belongs to animal TSE's which has been characterized histopathological changes in the CNS as with scrapie. It is newly diagnosed prion disease, which has been never known until 1986 [110]. BSE became epidemic during the 1980s in the UK as a result of the changing rendering process and allowing to enter the prion contaminated product to cattle nutrition, and it is estimated that the exposure began in the early 1980s [110]. Having transmitted to human and causing a new variant of Creutzfeldt‐Jakob disease (CJD) [62] which is a human prion disease acquired from consumption of the meat products of the BSE diseased cattle [111], BSE has been regarded by the World Health Organization [112] as zoonotic. Unlike CJD, vCJD has diagnosed in younger people in the UK [113], latter in France [114]. Up to 2003, 135 vCJD cases have reported from the UK and 6 cases from France (reviewed in reference [115]).

BSE could transmit to sheep and goats by experimental routes [116] and development of the disease seemed to be affected by the PRNP genotype of the individual [88, 117]; furthermore, it was reported that BSE in goats can be occur in natural conditions [118, 119].

Because of the zoonotic potential and the ability to spread between species of the BSE, it has raised the public health concerns and enforced to governments to take control and preventive measures; moreover, researchers have intensified to reveal the genetic background of the disease.

Early studies on association between PRNP genotype of cattle and development of the BSE have focused on two known polymorphisms; the HindII restriction site and an octapeptide repeated sequence in the coding region of the cattle PRNP, but no relationship between these genotypes and BSE infection has found [120, 121]; however, although lack of detailed genetic information, some clues were obtained suggesting that BSE might be in linkage with host PRNP genotype [9].

In the following years, hundreds of nucleotide changes and insertions/deletions (indel) were identified in bovine PRNP [13, 122, 123, 124], including a 12 base pair (bp) indel within the intron 1 and a 23 bp indel within the promoter region [13, 122]. Case control studies showed that distribution of these two indel polymorphisms were different between healthy and BSE affected cattle and insertion alleles presumably connected with disease resistance [13]; moreover, it has demonstrated that insertion alleles related to the lower prion protein level compared with deletion alleles and may differentiate of the BSE incubation period [15]. Further studies have supported the relationship between BSE resistance and 23 bp/12 bp indel genotypes that are given in Table 6.

		23 bp indel genotypes
	Healthy cattle				BSE‐affected cattle
Breed	n	in/in	in/del	del/del	n	in/in	in/del	del/del	References
Pooled German breeds	48	0.210	0.440	0.350	43	0.050	0.440	0.510	[13]
UK Holstein	276	0.047	0.489	0.464	363	0.013	0.410	0.554	[16]
German Holstein	313	0.147	0.473	0.380	127	0.079	0.465	0.457	[16]
German Brown	87	0.448	0.414	0.138	43	0.140	0.651	0.209	[16]
German Fleckvieh	136	0.103	0.434	0.463	106	0.066	0.396	0.538	[16]
Pooled German and Switzerland breeds	574	0.160	0.470	0.370	670	0.090	0.470	0.450	[17]
Pooled Japanese breeds	464	0.071	0.440	0.489	6	0.000	0.333	0.467	[20]
Pooled Czech breeds	81	0.235	0.543	0.222	26	0.077	0.538	0.385	[125]
		12 bp indel genotypes
	Healthy cattle				BSE‐affected cattle
Breed	n	in/in	in/del	del/del	n	in/in	in/del	del/del	References
Pooled German breeds	48	0.210	0.560	0.230	43	0.090	0.470	0.440	[13]
UK Holstein	270	0.111	0.519	0.370	350	0.051	0.454	0.494	[16]
German Holstein	309	0.220	0.498	0.282	125	0.144	0.456	0.400	[16]
German Brown	90	0.744	0.222	0.033	43	0.419	0.512	0.070	[16]
German Fleckvieh	137	0.153	0.453	0.394	106	0.085	0.462	0.453	[16]
Pooled German and Switzerland breeds	574	0.230	0.460	0.310	670	0.170	0.490	0.340	[17]
Pooled Japanese breeds	476	0.095	0.468	0.437	6	0.000	0.333	0.467	[20]
Pooled Czech breeds	81	0.358	0.444	0.198	26	0.231	0.462	0.308	[125]

Table 6.

The distribution of the PRNP 23 bp indel and 12 bp indel genotypes according to breeds, in both healthy and BSE‐affected cattle.

Although the clear association has been shown between PRNP indel genotypes and BSE incidence, there are some paradoxical situations at breed level, for example, it was reported that although Brown breeds have higher allelic frequency of insertion alleles, at the same time, these breeds have higher prevalence of BSE [17]. However, beside of the primary measures for prevention from circulation of BSE agents and exposure to both animal and human, selective breeding can offer a secondary strategy to eliminate the BSE.

Apart from classical BSE, two more types of the disease have been diagnosed by histopathological examinations; H‐type and L‐type, both of two types classified as atypical BSE and have been observing sporadically. While H‐type BSE characterized with higher molecular mass [126], L‐type BSE which is also named as bovine amyloidotic spongiform encephalopathy (BASE), characterized with lower molecular mass and has diverse glycopattern of pathogenic prion proteins [127].

It is reported that PRNP 23 and 12 bp indel polymorphism do not provide the genetic resistance, neither to naturally occurring atypical BSE nor to experimentally inoculated other TSEs [16]. Although very limited data, several atypical cases with extremely rare [128] glutamate to lysine mutation in codon 211 (E211K), which is homologous with human E200K mutation in the PRNP gene, has determined, suggesting that association to atypical BSE resistance may be exist [129, 130], but could not confirm by following studies [131, 132]. Transmissibility of the H‐type atypical BSE to cattle which is carrying the E211K mutation was demonstrated [133], on the other hand, some evidences have obtained that the E211K is a germ line mutation, thus, may cause inherited BSE that can be transmitted genetically [130].

5. Resistance in water buffaloes

During the BSE epidemic in 1980s, it can be assumed that BSE and/or scrapie contaminated by‐products most likely have entered in to water buffalo (Bubalus bubalis) nutrition systems, as well. EU member states have approximately 409 thousand of buffaloes, where 90% of those have been reared in Italy [134]. Between 2001 and 2005, 128 BSE cases in cattle have been reported from Italy [135]. Along with cattle, bison, sheep, goats and some exotic ruminants, water buffaloes have been considered as TSE‐related risk factors [136]; nevertheless, no BSE or any other TSE has ever been reported in water buffaloes [137] neither in Italy nor the rest of the world.

Only few studies on indel polymorphisms of the water buffalo PRNP gene have conducted to compare with cattle PRNP. According to the results, 12 and 23 bp indel polymorphisms have been existed in water buffalo, as well. Furthermore, insertion alleles which are relate to BSE resistance have observed more frequent than those in cattle [138–141] that is given in Table 7.

			23 bp indel alleles		12 bp indel alleles		References
Country	Breed	n	In %	Del %	In %	Del %	References
Turkey	Anatolian Buffalo	106	92	8	86	14	[138]
Pakistan	Nili Buffalo	66	94	6	86	14	[139]
	Ravi Buffalo	39	97	3	83	17
	Azikheli Buffalo	20	100	0	95	5
	Kundhi Buffalo	34	97	3	88	12
	Nili Ravi Buffalo	122	94	6	87	13
Indonesia	River Buffalo	14	100	0	100	0	[142]
Thai	River Buffalo	45	53	47	84	16	[142]
Germany	River Buffalo	11	100	0	100	0	[140]
Poland	River Buffalo	29	100	0	100	0	[140]
Turkey	Anatolian Buffalo	89	100	0	100	0	[141]
Turkey	Murrah Buffalo	20	100	0	100	0	[141]

Table 7.

23 and 12 bp allele frequencies of healthy water buffaloes reared in Asian and European states.

As seen in Table 7, almost all buffalo breeds, except Thai river buffalo, are carrying mostly insertion alleles either at 23 or 12 bp indel loci. This may be an explanation for why buffaloes putatively resistant to BSE.

The SPRN gene, which belongs to the prion protein gene family, encodes the shadow protein. Shadow protein shares characteristic features with cellular prion protein, suggesting the existence of a functional relation with prion proteins [143]. A comparative study revealed that the SPRN gene has species‐specific indel polymorphisms in cattle and buffaloes and causes different promoter activity and expression levels [144]. Furthermore, according to the results of more recent study, molecular structure of buffalo cellular prion protein is different from cattle, but similar to those of rabbits, dog and horse which are considered low susceptible to TSEs [145]. These molecular and structural differences may be another explanation with regard to TSEs resistance in buffaloes.

References

1. Prusiner SB, Prions. Proceedings of the National Academy of Sciences USA. 1998;95:13363–13383.
2. Hopp P, Ulvund MJ, Jarp J. A case‐control study on scrapie in Norwegian sheep flocks. Preventive Veterinary Medicine. 2001;51:183–198.
3. Bucalossi C, Cosseddu G, D'Agostino C, Di Bari MA, Chiappini B, Conte M, Rosone F, De Grossi L, Scavia G, Agrimi U, Nonno R, Vaccari G. Assessment of the genetic susceptibility of sheep to scrapie by protein misfolding cyclic amplification and comparison with experimental scrapie transmission studies. Journal of Virology. 2011;85(16):8386–92. doi:10.1128/JVI.00241‐11
4. Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T, Uphill JB, Goldstein D, Alpers M, Fisher EM, Collinge J. Balancing selection at the prion protein gene consistent with prehistoric kuru like epidemics. Science. 2003;300:640–643. doi:10.1126/science.1083320
5. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 2004;364:527–529. doi:10.1016/S0140‐6736(04)16811‐6
6. Tranulis MA. Influence of the prion protein gene, PrnP, on scrapie susceptibility in sheep. Acta Pathologica, Microbiologica et Immunologica Scandinavica. 2002;101:33–42.
7. Tongue SC, Wilesmith JW, Cook CJ. Frequencies of prion protein (PrP) genotypes and distribution of ages in 15 scrapie‐affected flocks in Great Britain. Veterinary Record. 2004;154: 9–16.
8. Goldmann W, Hunter N, Benson G, Foster JD, Hope J. Different scrapie‐associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the sip gene. Journal of General Virology. 1991a;72:2411–2417. doi:10.1099/0022‐1317‐72‐10‐2411
9. Neibergs HL, Ryan AM, Womack JE, Spooner RL, Williams JL. Polymorphism analysis of the prion gene in BSE‐affected and unaffected cattle. Animal Genetics. 1994;25(5):313–17.
10. Hunter N, Foster JD, Goldmann W, Stear MJ, Hope J, Bostock C. Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes. Archives of Virology 1996;141:809–824. doi:10.1007/BF01718157
11. Walawski K, Czarnik U. Prion protein octapeptide‐repeat polymorphism in Polish Black and White cattle. Journal of Applied Genetics. 2003;44:191–195.
12. Heaton MP, Leymaster KA, Freking BA, Hawk DA, Smith TP, Keele JW, Snelling WM, Fox JM, Chitko‐McKown CG, Laegreid WW. Prion gene sequence variation within diverse groups of U.S. sheep, beef cattle, and deer. Mammalian Genome. 2003;14:765–777. doi:10.1007/s00335‐003‐2283‐y
13. Sander P, Hamann H, Pfeiffer I, Wemheuer W, Brenig B, Groschup MH, Ziegler U, Distl O, Leeb T. Analysis of sequence variability of the bovine prion protein gene (PRNP) in German cattle breeds. Neurogenetics. 2004;5(1):19–25. doi:10.1007/s10048‐003‐0171‐y
14. Seabury CM, Womack JE, Pedrahita J, Derr JN. Comparative PRNP genotyping of U.S. cattle sires for potential association with BSE. Mammalian Genome. 2004;15(10):828–833. doi:10.1007/s00335‐004‐2400‐6
15. Sander P, Hamann H, Drögemüller C, Kashkevich K, Schiebel K, Leeb T. Bovine prion protein gene (PRNP) promoter polymorphisms modulate PRNP expression and may be responsible for differences in bovine spongiform encephalopathy susceptibility. Journal of Biological Chemistry 2005;280(45):37408–14. doi:10.1074/jbc. M506361200
16. Juling K, Schwarzenbacher H, Williams JL, Fries R. A major genetic component of BSE susceptibility. BMC Biology. 2006;4:33. doi:10.1186/1741‐7007‐4‐33
17. Haase B, Doherr MG, Seuberlich T, Drögemüller C, Dolf G, Nicken P, Schiebel K, Ziegler U, Groschup MH, Zurbriggen A, Leeb T. PRNP promoter polymorphisms are associated with BSE susceptibility in Swiss and German cattle. BMC Genetics. 2007;8:15. doi:10.1186/1471‐2156‐8‐15
18. Kashkevich K, Humeny A, Ziegler U, Groschup MH, Nicken P, Leeb T, Fischer C, Becker CM, Schiebel K. Functional relevance of DNA polymorphisms within the promoter region of the prion protein gene and their association to BSE infection. FASEB Journal. 2007;21:1547–1555.
19. Brunelle BW, Hamir AN, Baron T, Biacabe AG, Richt JA, Kunkle RA, Cutlip RC, Miller JM, Nicholson EM. Polymorphisms of the prion gene promoter region that influence classical bovine spongiform encephalopathy susceptibility are not applicable to other transmissible spongiform encephalopathies in cattle. Journal of Animal Science. 2007;85(12):3142–47. doi:10.2527/jas.2007‐0208
20. Nakamitsu S, Miyazawa T, Horiuchi M, Onoe S, Ohoba Y, Kitagawa H, Ishiguro N. Sequence variation of bovine prion protein gene in Japanese cattle (Holstein and Japanese Black). The Journal of Veterinary Medical Science. 2006;68(1):27–33. doi:JST.JSTAGE/jvms/68.27
21. Jeong BH, Lee YJ, Kim NH, Carp RI, Kim YS. Genotype distribution of the prion protein gene (PRNP) promoter polymorhisms in Korean cattle. Genome. 2006;49:1539–1544. doi:10.1139/g06‐110
22. Czarnik U, Zabolewicz T, Strychalski J, Grzybowski G, Bogusz M, Walawski K. Deletion/insertion polymorphism of the prion protein gene (PRNP) in Polish Holstein‐Friesian cattle. Journal of Applied Genetics. 2007;48(1):69–71. doi:10.1007/BF03194659
23. Kerber AR, Hepp D, Passos DT, Weimer TA. Polymorphisms of two indels at the PRNP gene in three beef cattle herds. Biochemical Genetics. 2007;46:1–7. doi:10.1007/s10528‐007‐9113‐y
24. Creutzfeldt HG. Über eine eigenartige herdförmige Erkrankung des Zentralnervensystems. Z Gesamte Neurol Psychiatr. 1920;57:1–19.
25. Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea. The endemic occurrence of “kuru” in the native population. The New England Journal of Medicine. 1957;257:974–978.
26. Richardson EP, Masters CL. The nosology of Creutzfeldt‐Jakob disease and conditions related to the accumulation of PrPCJD in the nervous system. Brain Pathology. 1995;5:33–4.
27. Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt‐Jakob disease. Nature. 1991;352:340–342. doi:10.1038/352340a0
28. Windl O, Dempster M, Estibeiro JP, Lathe R, de Silva R, Esmonde T, Will R, Springbett A, Campbell TA, Sidle KC, Palmer MS, Collinge J. Genetic basis of Creutzfeldt‐Jakob disease in the United Kingom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Human Genetics. 1996;98:259–264.
29. Shibuya S, Higuchi J, Shin RW, Tateishi J, Kitamoto T. Protective prion protein polymorphisms against sporadic Creutzfeldt‐Jakob disease. Lancet. 1998;351:419.
30. Detwiler LA. Scrapie. Revue Scientifique Et Technique‐Office International Des Epizooties. 1992;11(2):491–537.
31. M'Gowan JP. Investigation into the disease of sheep called “Scrapie” (Traberkrankheit [or] La Tremblante): with reference to its association with sarcosporidiosis. William Blackwood & Sons; 1914. 116P.
32. Parry HB. Scrapie: a transmissible hereditary disease of sheep. Nature. 1960;185:441–43.
33. Parry HB. Scrapie: a transmissible and hereditary disease of sheep. Heredity. 1962;17:75–105.
34. Dickinson AG, Stamp JT, Renwick CC. Maternal and lateral transmission of scrapie in sheep. Journal of Comparative Pathology. 1974;84(1):19–25. doi:10.1016/0021‐9975(74)90023‐1
35. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science.1982;216(4542):136–44. doi:10.1126/science.6801762
36. Dickinson AG, Meikle VM, Fraser H. Identification of a gene which controls the incubation period of some strains of scrapie agent in mice. Journal of Comparative Pathology. 1968;78(3):293–99. doi:10.1016/0021‐9975(68)90005‐4
37. Foster J, Dickinson A. The unusual properties of CH1641, a sheep‐passaged isolate of scrapie. Veterinary Record 1988;123:5–8. doi:10.1136/vr.123.1.5
38. Hope J, Hunter N. Scrapie‐associated fibrils, PrP protein and the sinc gene. Ciba Foundation Symposium. 1988;135:146–63.
39. Hunter N, Foster JD, Dickinson AG, Hope J. Linkage of the gene for the scrapie‐associated fibril protein (PrP) to the sip gene in Cheviot Sheep. Veterinary Record. 1989;124(14):364–66.
40. Goldmann W, Hunter N, Foster JD, Salbaum JM, Beyreuther K, Hope J. Two alleles of a neural protein gene linked to scrapie in sheep. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(7):2476–80.
41. Iannuzzi L, Palomba R, Di Meo GP, Perucatti A, Ferrara L. Comparative FISH‐Mapping of the prion protein gene (PRNP) on cattle, river buffalo, sheep and goat chromosomes. Cytogenetics and Cell Genetics. 1998;81:202–4. doi:10.1159/0000 15030
42. Clouscard C, Beaudry P, Elsen JM, Milan D, Dussaucy M, Bounneau C, Schelcher F, Chatelain J, Launay JM, Laplanche JL. Different allelic effects of the codons 136 and 171 of the prion protein gene in sheep with natural scrapie. Journal of General Virology. 1995;76:2097–2101.
43. Laplanche JL, Chatelain J, Westaway D, Thomas S, Dussaucy M, Brugere‐Picoux J, Launay M. PrP polymorphisms associated with natural scrapie discovered by denaturing gradient gel electrophoresis. Genomics. 1993;15(1):30–37. doi:10.1006/geno. 1993.1006
44. Hunter N, Goldmann W, Benson G, Foster JD, Hope J. Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie. Journal of General Virology 1993;74:1025–31. doi:10.1099/0022‐1317‐74‐6‐1025
45. Belt PB, Muileman IH, Schreuder BE, Bos‐de Ruijter J, Gielkens AL, Smits MA. Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. Journal of General Virology 1995; 76: 509–17. doi:10.1099/0022‐1317‐76‐3‐509
46. Baylis M, Chihota C, Stevenson E, Goldmann W, Smith A, Sivam K, Tongue S, Gravenor MB. Risk of scrapie in British sheep of different prion protein genotype. Journal of General Virology. 2004;85:2735–40. doi:10.1099/vir.0.79876‐0
47. Ikeda T, Horiuchi M, Ishiguro N, Muramatsu Y, Kai‐Uwe GD, Shinagawa M. Amino acid polymorphisms of PrP with reference to onset of scrapie in Suffolk and Corriedale sheep in Japan. Journal of General Virology. 1995;76:2577–81. doi:10.1099/0022‐1317‐76‐10‐2577
48. Groschup MH, Lacroux C, Buschmann A, Lühken G, Mathey J, Eiden M, Lugan S, Hoffmann C, Espinosa JC, Baron T, Torres JM, Erhardt G, Andreoletti O. Classic scrapie in sheep with the ARR/ARR prion genotype in Germany and France. Emerging Infectious Diseases. 2007;13(8);1201–7. doi:10.3201/eid1308.070077
49. Tranulis MA, Osland A, Bratberg B, Ulvund MJ. Prion protein gene polymorphisms in sheep with natural scrapie and healthy controls in Norway. Journal of General Virology. 1999;80:1073–77. doi:10.1099/0022‐1317‐80‐4‐1073
50. Baylis M, Goldmann W, Houston F, Cairns D, Chong A, Ross A, Smith A, Hunter N, McLean AR. Scrapie epidemic in a fully PrP‐genotyped sheep flock. The Journal of General Virology. 2002;83:2907–14. doi:10.1099/0022‐1317‐83‐11‐2907
51. Saunders GC, Cawthraw S, Mountjoy SJ, Hope J, Windl O. PrP genotypes of atypical scrapie cases in Great Britain. Journal of General Virology. 2006;87:3141–49. doi:10.1099/vir.0.81779‐0
52. François D, Elsen JM, Barillet F, Lajous D, Eychenne F, Palhière I. Breeding sheep for scrapie resistance CIHEAM. 2003;55:29–35.
53. Fediaevsky A, Calavas D, Gasqui P, Moazami‐Goudarzi K, Laurent P, Arsac J‐N, Ducrot C, Moreno C. Quantitative estimation of genetic risk for atypical scrapie in french sheep and potential consequences of the current breeding programme for resistance to scrapie on the risk of atypical scrapie. Genetics Selection Evolution 2010;42(1):1–7. doi:10.1186/1297‐9686‐42‐14
54. O'Doherty E, Healy A, Aherne M, Hanrahan JP, Weavers E, Doherty M, Roche JF, Gunn M, Sweeney T. Prion Protein (PrP) gene polymorphisms associated with natural scrapie cases and their flock‐mates in Ireland. Research in Veterinary Science. 2002;73(3):243–50. doi:10.1016/S0034‐5288(02)00073‐5
55. Acutis PL, Sbaiz L, Verburg F, Riina MV, Ru G, Moda G, Caramelli M, Bossers A. Low frequency of the scrapie resistance‐associated allele and presence of lysine‐171 allele of the prion protein gene in Italian Biellese ovine breed. The Journal of General Virology. 2004;85:3165–72. doi:10.1099/vir.0.80053‐0
56. Thorgeirsdottir S, Sigurdarson S, Thorisson HM, Georgsson G, Palsdottir A. PrP gene polymorphism and natural scrapie in Icelandic Sheep. Journal of General Virology. 1999;80:2527–34.
57. Billinis C, Psychas V, Leontides L, Spyrou V, Argyroudis S, Vlemmas I, Leontides S, Sklaviadis T, Papadopoulos O. Prion protein gene polymorphisms in healthy and scrapie‐affected sheep in Greece. The Journal of General Virology. 2004;85:547–54. doi:10.1099/vir.0.19520‐0
58. Harrington NP, O'Rourke KI, Feng Y, Rendulich J, Difruscio C, Balachandran A. Prion genotypes of scrapie‐infected Canadian Sheep 1998‐2008. Canadian Journal of Veterinary Research. 2010;74(3):228–232.
59. Gibbs CJ, Gajdusek DC. Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Nature. 1972;236(5341):73–74. doi:10.1038/236073a0
60. Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 1994;343(1306):405–11. doi:10.1098/rstb.1994.0036
61. Kimberlin RH, Walker CA. Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. Journal of General Virology. 1978;39(3):487–96. doi:10.1099/0022‐1317‐39‐3‐487
62. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature. 1997;389(6650):498–501. doi:10.1038/39057
63. Nathanson N, Wilesmith J, Griot C, Bovine spongiform encephalopathy (BSE): Causes and consequences of a common source epidemic. American Journal of Epidemiology. 1997;145(11):959–69. doi:10.1093/aje/kwi188
64. Comoy EE, Mikol J, Luccantoni‐Freire S, Correia E, Lescoutra‐Etchegaray N, Durand V, Dehen C, Andreoletti O, Casalone C, Richt JA, Greenlee JJ, Baron T,.Benestad SL, Brown P, Deslys J‐P. 2015. Transmission of scrapie prions to primate after an extended silent incubation period. Nature. 2015;5;11573 Scientific Reports doi:10.1038/srep11573
65. DEFRA. National Scrapie Plan for Great Britaint. 2001;1 (July):1–28.
66. Commission Decision, “Laying down minimum requirements for the establishment of breeding programmes for resistance to transmissible spongiform encephalopathies in sheep.” Official Journal 2003/100/E:L41–45.
67. EFSA. Scientific opinion on the scrapie situation in the EU after 10 years of monitoring and control in sheep and goats. EFSA Journal, 2014;12(7). doi:10.2903/j.efsa. 2014.3781
68. Hunter N, Cairns D. Scrapie‐free merino and poll dorset sheep from Australia and New Zealand have normal frequencies of scrapie‐susceptible PrP genotypes. Journal of General Virology. 1998;79:2079–82. doi:10.1099/0022‐1317‐79‐8‐2079
69. Ianella P, McManus CM, Caetano AR, Paiva SR. PRNP Haplotype and genotype frequencies in Brazilian sheep: Issues for conservation and breeding programs. Research in Veterinary Science. 2012;93(1):219–25. doi:10.1016/j.rvsc.2011.06.025
70. Gootwine E, Abdulkhaliq A, Jawasreh KIZ, Valle Zárate A. Screening for polymorphism at the prion protein (PrP) locus (PRNP) in Awassi and Assaf populations in Israel, the Palestinian Authority and Jordan. Small Ruminant Research. 2008:77(1):80–83. doi:10.1016/j.smallrumres.2008.02.008
71. Yaman Y, Soysal M, Ün C. Evaluation of the genetic resistance status to classical and atypical scrapie in Karacabey merino rams. Turkish Journal of Veterinary and Animal Sciences. 2015;39:736–40. doi:10.3906/vet‐1507‐36
72. Lühken G, Lipsky S, Peter C, Erhardt E. Prion protein polymorphisms in autochthonous European sheep breeds in respect to scrapie eradication in affected flocks. Small Ruminant Research. 2008:75(1):43–47. doi:10.1016/j.smallrumres.2007.07.010
73. Tsunoda K, Namikawa T, Sato K, Hasnath MA, Nyunt MM, Rajbandary HB, Loc CB, Zanchiv Ts, Chang H, Sun W, Dorji T. Prion protein polymorphisms and estimation of risk of scrapie in East Asian sheep. Biochemical Genetics. 2010;48(1–2): 13–25. doi:10.1007/s10528‐009‐9287‐6
74. Chelle PL. A case of trembling in the goat. Academie Veterinaire de France Bulletin. 1942;15:294–295.
75. EFSA. Scientific opinion on genetic TSE resistance in goats in all European Union. EFSA Journal. 2009;7(11):1–42. doi:10.2903/j.efsa.2009.1371
76. Wood JN, Done SH, Pritchard GC, Wooldridge MJ. Natural scrapie in goats: Case histories and clinical signs. Veterinary Record. 1992;131(4):66–68. doi:10.1136/vr.131.4.66
77. Sofianidis G, Psychas V, Billinis C, Spyrou V, Argyroudis S, Papaioannou N, Vlemmas I. Histopathological and immunohistochemical features of natural goat scrapie. Journal of Comparative Pathology. 2006;135(2–3):116–29. doi:10.1016/j.jcpa. 2006.06.004
78. Papasavva‐Stylianou P, Kleanthous M, Toumazos P, Mavrikiou P, Loucaides P. Novel polymorphisms at codons 146 and 151 in the prion protein gene of Cyprus goats, and their association with natural scrapie. Veterinary Journal. 2007;173(2):459–62. doi:10.1016/j.tvjl.2005.09.013
79. Brotherston JG, Renwick CC, Stamp JT, Zlotnik I, Pattison IH. Spread of scrapie by contact to goats and sheep. Journal of Comparative Pathology. 1968;78:9–17. doi:10.1016/0021‐9975(68)90107‐2
80. Billinis C, Panagiotidis CH, Psychas V, Argyroudis S, Nicolaou A, Leontides S, Papadopoulos O, Sklaviadis T. Prion protein gene polymorphisms in natural goat scrapie. Journal of General Virology. 2002;83;713–21. doi:10.1099/0022‐1317‐83‐3‐713
81. Toumazos P, Alley MR. Scrapie in goats in Cyprus. New Zealand Veterinary Journal 1989;37(4):160–62. doi:10.1080/00480169.1989.35595
82. Vaccari G, Panagiotidis CH, Acin C, Peletto S, Barillet F, Acutis P, Bossers A, Langeveld J, van Keulen L, Sklaviadis T, Badiola JJ, Andreéoletti O, Groschup MH, Agrimi U, Foster J, Goldmann W. State‐of‐the‐art review of goat TSE in the European Union, with special emphasis on PRNP genetics and epidemiology. Veterinary Research. 2009;40(5):48. doi:10.1051/vetres/2009031
83. Vaccari G, Di Bari MA, Morelli L, Nonno R, Chiappini B, Antonucci G, Marcon S, Esposito E, Fazzi P, Palazzini N, Troiano P, Petrella A, Di Guardo G, Agrimi U. Identification of an allelic variant of the goat PrP gene associated with resistance to scrapie. Journal of General Virology. 2006;87:1395–1402. doi:10.1099/vir.0.81485‐0
84. Acutis PL, Colussi S, Santagada G, Laurenza C, Maniaci MG, Riina MV, Peletto S, Goldmann W, Bossers A, Caramelli M, Cristoferi I, Maione S, Sacchi P, Rasero R. Genetic variability of the PRNP gene in goat breeds from northern and southern Italy. Journal of Applied Microbiology. 2008;104(6):1782–89. doi:10.1111/j.1365‐2672.2007.03703.x
85. Goldmann W, Perucchini M, Smith A, Hunter N. Genetic variability of the PrP gene in a goat herd in the UK. Veterinary Record. 2004;155:177–178.
86. Goldmann W, Ryan K, Stewart P, Parnham D, Xicohtencatl R, Fernandez N, Saunders G, Windl O, González L, Bossers A, Foster J. Caprine prion gene polymorphisms are associated with decreased incidence of classical scrapie in goat herds in the United Kingdom. Veterinary Research. 2011;42:110. doi:10.1186/1297‐9716‐42‐110
87. Serrano C, Hammouchi M, Benomar A, Lyahyai J, Ranera B, Acín C, el Hamidi M, Monzón M, Badiola JJ, Tligui N, Zaragoza P, Martín‐Burriel I. PRNP haplotype distribution in Moroccan goats. Animal Genetics. 2009;40(4):565–68. doi:10.1111/j.1365‐2052.2009.01873.x
88. Goldmann W, Martin T, Foster J, Hughes S, Smith G, Hughes K, Dawson M, Hunter N. Novel polymorphisms in the caprine PrP gene: A codon 142 mutation associated with scrapie incubation period. Journal of General Virology. 1996;77:2885–91. doi:10.1099/0022‐1317‐77‐11‐2885
89. Barillet F, Mariat D, Amigues Y, Faugeras R, Caillat H, Moazami‐Goudarzi K, Rupp R, Babilliot JM, Lacroux C, Lugan S, Schelcher F, Chartier C, Corbière F, Andréoletti O, Perrin‐Chauvineau C. Identification of seven haplotypes of the caprine PrP gene at codons 127, 142, 154, 211, 222 and 240 in French alpine and saanen breeds and their association with classical scrapie. Journal of General Virology. 2009;90:769–76. doi:10.1099/vir.0.006114‐0
90. White SN, Reynolds JO, Waldron DF. Extended scrapie incubation time in goats singly heterozygous for PRNP S146 or K222. Gene. 2012;501:49–51. doi:10.1016/j. gene.2012.03.068
91. Wopfner F, Weidenhöfer G, Schneider R, von Brunn A, Gilch S, Schwarz TF, Werner T, Schätzl HM. Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein. Journal of Molecular Biology. 1999;289(5):1163–78. doi:10.1006/jmbi.1999.2831
92. Zhou RY, Li XL, Li LH, Wang HY, Lü JG. Polymorphism of the PRNP gene in the main breeds of indigenous Chinese goats. Archives of Virology. 2008;153:979–82. doi:10.1007/s00705‐008‐0074‐1
93. Acutis PL, Bossers A, Priem J, Riina MV, Peletto S, Mazza M, Casalone C, Forloni G, Ru G, Caramelli M. Identification of prion protein gene polymorphisms in goats from Italian scrapie outbreaks. The Journal of General Virology. 2006;87:1029–33. doi:10.1099/vir.0.81440‐0
94. Acutis PL, Martucci F, D'Angelo A, Peletto S, Colussi S, Maurella C, Porcario C, Iulini B, Mazza M, Dell'atti L, Zuccon F, Corona C, Martinelli N, Casalone C, Caramelli M, Lombardi G. Resistance to classical scrapie in experimentally challenged goats carrying mutation k222 of the prion protein gene. Veterinary Research. 2012;1:43–8. doi:10.1186/1297‐9716‐43‐8
95. Goldmann W, Chong A, Foster J, Hope J, Hunter N. The shortest known prion protein gene allele occurs in goats, has only three octapeptide repeats and is non‐pathogenic. Journal of General Virology. 1998;79:3173–3176.
96. Lan XY, Zhao HY, Li ZJ, Li AM, Lei CZ, Chen H, Pan CY. A novel 28‐bp insertion–deletion polymorphism within goat PRNP gene and its association with production traits in Chinese native breeds. Genome. 2012;55(7):547–52. doi:10.1139/g2012‐040
97. Benestad SL, Sarradin P, Thu B, Schönheit J, Tranulis MA, Bratberg B. Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. The Veterinary Record. 2003;153:202–8.
98. Bruce ME, Nonno R, Foster J, Goldmann W, Di Bari M, Esposito E, Benestad SL, Hunter N, Agrimi U. Nor98‐like sheep scrapie in the United Kingdom in 1989. Veterinary Record. 2007;160:665–66. doi:10.1136/vr.160.19.665
99. Webb PR, Powell L, Denyer M, Marsh S, Weaver C, Simmons MM, Johns E, Sheehan J, Horsfield P, Lyth C, Wilson C, Long A, Cawthraw S, Saunders GC, Spencer YI. A retrospective immunohistochemical study reveals atypical scrapie has existed in the United Kingdom since at least 1987. Journal of Veterinary Diagnostic Investigation. 2009;21(6):826–29.
100. Buschmann A, Biacabe A‐G, Ziegler U, Bencsik A, Madec J‐Y, Erhardt G, Lühken G, Baron T, Groschup MH. Atypical scrapie cases in Germany and France are identified by discrepant reaction patterns in BSE rapid tests. Journal of Virological Methods 2004;117(1):27–36. doi:10.1016/j.jviromet.2003.11.017
101. Everest SJ, Thorne L, Barnicle DA, Edwards JC, Elliott H, Jackman R, Hope J. Atypical prion protein in sheep brain collected during the British scrapie‐surveillance programme. Journal of General Virology. 2006;87:471–77. doi:10.1099/vir.0.81539‐0
102. Seuberlich T, Botteron C, Benestad SL, Brünisholz H, Wyss R, Kihm U, Schwermer H, Friess M, Nicolier A, Heim D, Zurbriggen A. Atypical scrapie in a Swiss goat and implications for transmissible spongiform encephalopathy surveillance. Journal of Veterinary Diagnostic Investigation. 2007;19(1):2–8. doi:10.1177/10406387070 1900102
103. Colussi S, Vaccari G, Maurella C, Bona C, Lorenzetti R, Troiano P, Casalinuovo F, Di Sarno A, Maniaci MG, Zuccon F, Nonno R, Casalone C, Mazza M, Ru G, Caramelli M, Agrimi U, Acutis PL. Histidine at codon 154 of the prion protein gene is a risk factor for Nor98 scrapie in goats. Journal of General Virology 2008;89:3173–76. doi:10.1099/vir.0.2008/004150‐0
104. Mitchell GB, O'Rourke KI, Harrington NP, Soutyrine A, Simmons MM, Dudas S, Zhuang D, Laude H, Balachandran A. Identification of atypical scrapie in Canadian Sheep. Journal of Veterinary Diagnostic Investigation. 2010;22(3):408–11. doi:10.1177/104063871002200310
105. Kittelberger R, Chaplin MJ, Simmons MM, Ramirez‐Villaescusa A, McIntyre L, MacDiarmid SC, Hannah MJ, Jenner J, Bueno R, Bayliss D, Black H, Pigott CJ, O'Keefe JS. Atypical scrapie/Nor98 in a sheep from New Zealand. Journal of Veterinary Diagnostic Investigation. 2010:22(6):863–75. doi:10.1177/10406387100220060
106. Moum T, Olsaker I, Hopp P, Moldal T, Valheim M, Moum T, Benestad SL. Polymorphisms at codons 141 and 154 in the ovine prion protein gene are associated with scrapie Nor98 cases. Journal of General Virology. 2005;86(1):231–35. doi:10.1099/vir.0.80437‐0
107. Lühken G1, Buschmann A, Brandt H, Eiden M, Groschup MH, Erhardt G. Epidemiological and genetical differences between classical and atypical scrapie cases. Veterinary Research. 2007;38(1):65–80. doi:10.1006/geno.1993.1006
108. Moreno CR, Moazami‐Goudarzi K, Laurent P, Cazeau G, Andreoletti O, Chadi S, Elsen JM, Calavas D. Which prp haplotypes in a French sheep population are the most susceptible to atypical scrapie? Archives of Virology. 2007;152(6):1229–32. doi:10.1007/s00705‐007‐0956‐7
109. Arsac JN, Andreoletti O, Bilheude J‐M, Lacroux C, Benestad SL, Taron T. Similar Biochemical signatures and prion protein genotypes in atypical scrapie and Nor98 cases, France and Norway. Emerging Infectious Diseases. 2007;13(1):58–65. doi:10.3201/eid1301.060393
110. Wilesmith JW. Bovine Spongiform encephalopathy and related Diseases: An epidemiological overview. New Zealand Veterinary Journal. 1994;42(1):1–8. doi:10.1080/00480169.1994.35774
111. Ghani AC, Donnelly CA, Ferguson NM, Anderson RM. The transmission dynamics of BSE and vCJD. Comptes Rendus Biologies. 2002;325(1):37–47. doi:10.1016/S1631‐0691(02)01389‐6
112. WHO “World Health Organization.” World Health Organization WHO/CDS/CS (WHO Consultation on public health and animal TSEs epidemiology, risk and research requirements: 2000;1–47.
113. Will RG, Ironside JW, Zeidler M, Estibeiro, Cousens SN, Smith PG, Alperovitch A, Poser S, Pocchiari M, Hofman M. A new variant of Creutzfeldt‐Jakob disease in the UK. Lancet. 1996;347(9006):921–25. doi:10.5555/uri:pii:S0140673696914129
114. Chazot G, Broussolle E, Lapras Cl, Blättler T, Aguzzi A, Kopp N. New variant of Creutzfeldt‐Jakob disease in a 26‐year‐old French man. Lancet (London, England) 1996;347(9009):1181. doi:10.5555/uri:pii:S0140673696906388
115. Will RG. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. British Medical Bulletin. 2003;66:255–65. doi:10.1093/bmb/66.1.255
116. Foster JD, Hope J, Fraser H. Transmission of bovine spongiform encephalopathy to sheep and goats. Veterinary Record. 1993;133(14):339–341. doi:10.1136/vr.133.14.339
117. Foster JD, Parnham D, Chong A, Goldmann W, Hunter N. Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats. Veterinary Record. 2001;148:165–71. doi:10.1136/vr.148.6.165
118. Eloit M, Adjou K, Coulpier M, Fontaine JJ, Hamel R, Lilin T, Messiaen S, Andreoletti O, Baron T, Bencsik A, Biacabe AG, Beringue V, Laude H, Le Dur A, Vilotte JL, Comoy E, Deslys JP, Grassi J, Simon S, Lantier F, Sarradin P. BSE agent signatures in a goat. Veterinary Record. 2005;156(16):523–24.
119. Spiropoulos J, Lockey R, Sallis RE, Terry LA, Thorne L, Holder TM, Beck KE, Simmons MM. Isolation of prion with BSE properties from farmed goat. Emerging Infectious Diseases. 2011;17(12):2253–61.
120. Goldmann W, Hunter N, Martin T, Dawson M, Hope J. Different forms of the bovine PrP gene have five or six copies of a short, G‐C‐rich element within the protein‐coding exon. Journal of General Virology. 1991b;72:201–204.
121. Hunter N, Goldmann w, G Smith, Hope j. Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland. Veterinary Record. 1994;135(17):400–403.
122. Hills D, Comincini S, Schlaepfer J, Dolf G, Ferretti L, Williams JL. Complete genomic sequence of the bovine prion gene (PRNP) and polymorphism in its promoter region. Animal Genetics. 2001;32(4):231–232. doi:10.1046/j.1365‐2052.2001.0769a.x
123. Hills D, Schlaepfer J, Comincini S, MacLean I, Dolf G, Ferretti L, Olsaker I, Williams JL. Sequence variation in the bovine and ovine PRNP genes. Animal Genetics. 2003;34(3):183–90. doi:10.1046/j.1365‐2052.2003.00977.x
124. Clawson ML, Heaton MP, Keele JW, Smith TP, Harhay GP, Laegreid WW. Prion gene haplotypes of U.S. Cattle. BMC Genetics. 2006;7:51. doi:10.1186/1471‐2156‐7‐51
125. Vernerova K, Tothova L, Mikova A, Vodrazka P, Simek B, Hanusova L, Citek J. BSE‐associated polymorphisms in the prion protein gene : An investigation. Journal of Animal Breeding and Genetics. 2014;131(5):403–408. doi:10.1111/jbg.12090
126. Biacabe AG, Laplanche JL, Ryder S, Baron T. Distinct molecular phenotypes in bovine prion diseases. EMBO Reports. 2004;5;110–15. doi:10.1038/sj.embor.7400054
127. Casalone C, Zanusso G, Acutis P, Ferrari S, Capucci L, Tagliavini F, Monaco S, Caramelli M. Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt‐Jakob disease. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(9):3065–70. doi:10.1073/pnas.0305777101
128. Heaton MP, Keele JW, Harhay GP, Richt JA, Koohmaraie M, Wheeler TL, Shackelford SD, Casas E, King DA, Sonstegard TS, Van Tassell CP, Neibergs HL, Chase CC Jr, Kalbfleisch TS, Smith TP, Clawson ML, Laegreid WW. Prevalence of the prion protein gene E211K variant in U.S. Cattle. BMC Veterinary Research. 2008;4:25. doi:10.1186/1746‐6148‐4‐25
129. Richt JA, Mark Hall S. BSE with case associated prion protein gene mutation. PLoS Pathogens. 2008;4(9):e1000156. doi:10.1371/journal.ppat.1000156
130. Nicholson EM, Brunelle BW, Richt JA, Kehrli ME Jr, Greenlee JJ. Identification of a heritable polymorphism in bovine PRNP associated with genetic transmissible spongiform encephalopathy: Evidence of heritable BSE. PloS One. 2008;3(8):e2912. doi:10.1371/journal.pone.0002912
131. Clawson ML, Richt JA, Baron T, Biacabe AG, Czub S, Heaton MP, Smith TP, Laegreid WW. Association of a bovine prion gene haplotype with atypical BSE. PloS One. 2008;3(3):e1830. doi:10.1371/journal
132. Gurgul A, Polak MP, Larska M, Słota E. PRNP and SPRN genes polymorphism in atypical bovine spongiform encephalopathy cases diagnosed in Polish Cattle. Journal of Applied Genetics. 2012;53(3):337–42. doi:10.1007/s13353‐012‐0102‐4
133. Greenlee JJ, Smith JD, West Greenlee MH, Nicholson EM. Clinical and pathologic features of H‐type bovine spongiform encephalopathy associated with e211k prion protein polymorphism. PloS One. 2012;7(6):e38678. doi:10.1371/journal.pone. 0038678
134. Anonymous. Agriculture statistics at regional level. [Internet]. 2015. http://ec.europa.eu/eurostat/statistics‐explained/index.php/Agriculture_statistics_at_ regional_level#Further_Eurostat_information [Accessed: 21.02.2015].
135. Ru G, Maurella C, Maroni Ponti A, Ingravalle F, Caramelli M. Epidemiological study of the decline of BSE in Italy. Veterinary Record. 2007;161(15):511–14. doi:10.1136/vr.161.15.511
136. Morley RS, Chen S, Rheault N. Assessment of the risk factors related to bovine spongiform encephalopathy. Revue scientifique et Technique. 2003;22(1):157–78.
137. Di Guardo G. BSE in buffaloes. The Veterinary Record. 2014;174(19):485. doi:10.1136/vr.g3177
138. Oztabak K, Ozkan E, Soysal I, Paya I, Un C. Detection of prion gene promoter and intron1 indel polymorphisms in Anatolian water buffalo (Bubalus bubalis). Journal of Animal Breeding and Genetics. 2009;126(6):463–67. doi:10.1111/j.1439‐0388.2009.00821.x
139. Imran M, Mahmood S, Babar ME, Hussain R, Yousaf MZ, Abid NB, Lone KP. PRNP gene variation in Pakistani cattle and buffaloes. Gene. 2012;505:180–85. doi:10.1016/j.gene.2012.05.038
140. Kobak P, Sablik S, Zukiewicz A, Syczewski A, Lechowicz W. Analysis of indel polymorphism of the PRNP gene in water buffalo, Bubalus bubalis. Acta Scientiarum Polonorum Zootechnica. 2014;13(1):51–56.
141. Yaman Y, Karadağ O, Ün C. Investigation of the prion protein gene (PRNP) polymorphisms in Anatolian, Murrah and crossbred water buffaloes (Bubalus bubalis). Tropical Animal Health and Production. doi:10.1007/s11250‐016‐1185‐4
142. Uchida L, Heriyanto A, Thongchai C, Hanh TT, Horiuchi M, Ishihara K, Tamura Y, Muramatsu Y. Genetic diversity in the prion protein gene (PRNP) of domestic cattle and water buffaloes in Vietnam, Indonesia and Thailand. Journal of Veterinary Medical Science. 2014;76(7):1001–8.
143. Premzl M, Sangiorgio L, Strumbo B, Marshall Graves JA, Simonic T, Gready JE. Shadoo, a new protein highly conserved from fish to mammals and with similarity to prion protein. Gene. 2003;314:89–102. doi:10.1016/S0378‐1119(03)00707‐8
144. Zhao H, Liu LL, Du SH, Wang SQ, Zhang YP. Comparative analysis of the shadoo gene between cattle and buffalo reveals significant differences. PloS One. 2012;7(10):e46601. doi:10.1371/journal.pone.0046601
145. Zhang J, Wang F, Chatterjee S. Molecular dynamics studies on the buffalo prion protein. Journal of Biomolecular Structure & Dynamics. 2015;34(4):762–777. doi:10.1080/07391102.2015.1052849

[1] 1. Prusiner SB, Prions. Proceedings of the National Academy of Sciences USA. 1998;95:13363–13383.

[2] 2. Hopp P, Ulvund MJ, Jarp J. A case‐control study on scrapie in Norwegian sheep flocks. Preventive Veterinary Medicine. 2001;51:183–198.

[3] 3. Bucalossi C, Cosseddu G, D'Agostino C, Di Bari MA, Chiappini B, Conte M, Rosone F, De Grossi L, Scavia G, Agrimi U, Nonno R, Vaccari G. Assessment of the genetic susceptibility of sheep to scrapie by protein misfolding cyclic amplification and comparison with experimental scrapie transmission studies. Journal of Virology. 2011;85(16):8386–92. doi:10.1128/JVI.00241‐11

[4] 4. Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T, Uphill JB, Goldstein D, Alpers M, Fisher EM, Collinge J. Balancing selection at the prion protein gene consistent with prehistoric kuru like epidemics. Science. 2003;300:640–643. doi:10.1126/science.1083320

[5] 5. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 2004;364:527–529. doi:10.1016/S0140‐6736(04)16811‐6

[6] 6. Tranulis MA. Influence of the prion protein gene, PrnP, on scrapie susceptibility in sheep. Acta Pathologica, Microbiologica et Immunologica Scandinavica. 2002;101:33–42.

[7] 7. Tongue SC, Wilesmith JW, Cook CJ. Frequencies of prion protein (PrP) genotypes and distribution of ages in 15 scrapie‐affected flocks in Great Britain. Veterinary Record. 2004;154: 9–16.

[8] 8. Goldmann W, Hunter N, Benson G, Foster JD, Hope J. Different scrapie‐associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the sip gene. Journal of General Virology. 1991a;72:2411–2417. doi:10.1099/0022‐1317‐72‐10‐2411

[9] 9. Neibergs HL, Ryan AM, Womack JE, Spooner RL, Williams JL. Polymorphism analysis of the prion gene in BSE‐affected and unaffected cattle. Animal Genetics. 1994;25(5):313–17.

[10] 10. Hunter N, Foster JD, Goldmann W, Stear MJ, Hope J, Bostock C. Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes. Archives of Virology 1996;141:809–824. doi:10.1007/BF01718157

[11] 11. Walawski K, Czarnik U. Prion protein octapeptide‐repeat polymorphism in Polish Black and White cattle. Journal of Applied Genetics. 2003;44:191–195.

[12] 12. Heaton MP, Leymaster KA, Freking BA, Hawk DA, Smith TP, Keele JW, Snelling WM, Fox JM, Chitko‐McKown CG, Laegreid WW. Prion gene sequence variation within diverse groups of U.S. sheep, beef cattle, and deer. Mammalian Genome. 2003;14:765–777. doi:10.1007/s00335‐003‐2283‐y

[13] 13. Sander P, Hamann H, Pfeiffer I, Wemheuer W, Brenig B, Groschup MH, Ziegler U, Distl O, Leeb T. Analysis of sequence variability of the bovine prion protein gene (PRNP) in German cattle breeds. Neurogenetics. 2004;5(1):19–25. doi:10.1007/s10048‐003‐0171‐y

[14] 14. Seabury CM, Womack JE, Pedrahita J, Derr JN. Comparative PRNP genotyping of U.S. cattle sires for potential association with BSE. Mammalian Genome. 2004;15(10):828–833. doi:10.1007/s00335‐004‐2400‐6

[15] 15. Sander P, Hamann H, Drögemüller C, Kashkevich K, Schiebel K, Leeb T. Bovine prion protein gene (PRNP) promoter polymorphisms modulate PRNP expression and may be responsible for differences in bovine spongiform encephalopathy susceptibility. Journal of Biological Chemistry 2005;280(45):37408–14. doi:10.1074/jbc. M506361200

[16] 16. Juling K, Schwarzenbacher H, Williams JL, Fries R. A major genetic component of BSE susceptibility. BMC Biology. 2006;4:33. doi:10.1186/1741‐7007‐4‐33

[17] 17. Haase B, Doherr MG, Seuberlich T, Drögemüller C, Dolf G, Nicken P, Schiebel K, Ziegler U, Groschup MH, Zurbriggen A, Leeb T. PRNP promoter polymorphisms are associated with BSE susceptibility in Swiss and German cattle. BMC Genetics. 2007;8:15. doi:10.1186/1471‐2156‐8‐15

[18] 18. Kashkevich K, Humeny A, Ziegler U, Groschup MH, Nicken P, Leeb T, Fischer C, Becker CM, Schiebel K. Functional relevance of DNA polymorphisms within the promoter region of the prion protein gene and their association to BSE infection. FASEB Journal. 2007;21:1547–1555.

[19] 19. Brunelle BW, Hamir AN, Baron T, Biacabe AG, Richt JA, Kunkle RA, Cutlip RC, Miller JM, Nicholson EM. Polymorphisms of the prion gene promoter region that influence classical bovine spongiform encephalopathy susceptibility are not applicable to other transmissible spongiform encephalopathies in cattle. Journal of Animal Science. 2007;85(12):3142–47. doi:10.2527/jas.2007‐0208

[20] 20. Nakamitsu S, Miyazawa T, Horiuchi M, Onoe S, Ohoba Y, Kitagawa H, Ishiguro N. Sequence variation of bovine prion protein gene in Japanese cattle (Holstein and Japanese Black). The Journal of Veterinary Medical Science. 2006;68(1):27–33. doi:JST.JSTAGE/jvms/68.27

[21] 21. Jeong BH, Lee YJ, Kim NH, Carp RI, Kim YS. Genotype distribution of the prion protein gene (PRNP) promoter polymorhisms in Korean cattle. Genome. 2006;49:1539–1544. doi:10.1139/g06‐110

[22] 22. Czarnik U, Zabolewicz T, Strychalski J, Grzybowski G, Bogusz M, Walawski K. Deletion/insertion polymorphism of the prion protein gene (PRNP) in Polish Holstein‐Friesian cattle. Journal of Applied Genetics. 2007;48(1):69–71. doi:10.1007/BF03194659

[23] 23. Kerber AR, Hepp D, Passos DT, Weimer TA. Polymorphisms of two indels at the PRNP gene in three beef cattle herds. Biochemical Genetics. 2007;46:1–7. doi:10.1007/s10528‐007‐9113‐y

[24] 24. Creutzfeldt HG. Über eine eigenartige herdförmige Erkrankung des Zentralnervensystems. Z Gesamte Neurol Psychiatr. 1920;57:1–19.

[25] 25. Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea. The endemic occurrence of “kuru” in the native population. The New England Journal of Medicine. 1957;257:974–978.

[26] 26. Richardson EP, Masters CL. The nosology of Creutzfeldt‐Jakob disease and conditions related to the accumulation of PrPCJD in the nervous system. Brain Pathology. 1995;5:33–4.

[27] 27. Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt‐Jakob disease. Nature. 1991;352:340–342. doi:10.1038/352340a0

[28] 28. Windl O, Dempster M, Estibeiro JP, Lathe R, de Silva R, Esmonde T, Will R, Springbett A, Campbell TA, Sidle KC, Palmer MS, Collinge J. Genetic basis of Creutzfeldt‐Jakob disease in the United Kingom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Human Genetics. 1996;98:259–264.

[29] 29. Shibuya S, Higuchi J, Shin RW, Tateishi J, Kitamoto T. Protective prion protein polymorphisms against sporadic Creutzfeldt‐Jakob disease. Lancet. 1998;351:419.

[30] 30. Detwiler LA. Scrapie. Revue Scientifique Et Technique‐Office International Des Epizooties. 1992;11(2):491–537.

[31] 31. M'Gowan JP. Investigation into the disease of sheep called “Scrapie” (Traberkrankheit [or] La Tremblante): with reference to its association with sarcosporidiosis. William Blackwood & Sons; 1914. 116P.

[32] 32. Parry HB. Scrapie: a transmissible hereditary disease of sheep. Nature. 1960;185:441–43.

[33] 33. Parry HB. Scrapie: a transmissible and hereditary disease of sheep. Heredity. 1962;17:75–105.

[34] 34. Dickinson AG, Stamp JT, Renwick CC. Maternal and lateral transmission of scrapie in sheep. Journal of Comparative Pathology. 1974;84(1):19–25. doi:10.1016/0021‐9975(74)90023‐1

[35] 35. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science.1982;216(4542):136–44. doi:10.1126/science.6801762

[36] 36. Dickinson AG, Meikle VM, Fraser H. Identification of a gene which controls the incubation period of some strains of scrapie agent in mice. Journal of Comparative Pathology. 1968;78(3):293–99. doi:10.1016/0021‐9975(68)90005‐4

[37] 37. Foster J, Dickinson A. The unusual properties of CH1641, a sheep‐passaged isolate of scrapie. Veterinary Record 1988;123:5–8. doi:10.1136/vr.123.1.5

[38] 38. Hope J, Hunter N. Scrapie‐associated fibrils, PrP protein and the sinc gene. Ciba Foundation Symposium. 1988;135:146–63.

[39] 39. Hunter N, Foster JD, Dickinson AG, Hope J. Linkage of the gene for the scrapie‐associated fibril protein (PrP) to the sip gene in Cheviot Sheep. Veterinary Record. 1989;124(14):364–66.

[40] 40. Goldmann W, Hunter N, Foster JD, Salbaum JM, Beyreuther K, Hope J. Two alleles of a neural protein gene linked to scrapie in sheep. Proceedings of the National Academy of Sciences of the United States of America. 1990;87(7):2476–80.

[41] 41. Iannuzzi L, Palomba R, Di Meo GP, Perucatti A, Ferrara L. Comparative FISH‐Mapping of the prion protein gene (PRNP) on cattle, river buffalo, sheep and goat chromosomes. Cytogenetics and Cell Genetics. 1998;81:202–4. doi:10.1159/0000 15030

[42] 42. Clouscard C, Beaudry P, Elsen JM, Milan D, Dussaucy M, Bounneau C, Schelcher F, Chatelain J, Launay JM, Laplanche JL. Different allelic effects of the codons 136 and 171 of the prion protein gene in sheep with natural scrapie. Journal of General Virology. 1995;76:2097–2101.

[43] 43. Laplanche JL, Chatelain J, Westaway D, Thomas S, Dussaucy M, Brugere‐Picoux J, Launay M. PrP polymorphisms associated with natural scrapie discovered by denaturing gradient gel electrophoresis. Genomics. 1993;15(1):30–37. doi:10.1006/geno. 1993.1006

[44] 44. Hunter N, Goldmann W, Benson G, Foster JD, Hope J. Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie. Journal of General Virology 1993;74:1025–31. doi:10.1099/0022‐1317‐74‐6‐1025

[45] 45. Belt PB, Muileman IH, Schreuder BE, Bos‐de Ruijter J, Gielkens AL, Smits MA. Identification of five allelic variants of the sheep PrP gene and their association with natural scrapie. Journal of General Virology 1995; 76: 509–17. doi:10.1099/0022‐1317‐76‐3‐509

[46] 46. Baylis M, Chihota C, Stevenson E, Goldmann W, Smith A, Sivam K, Tongue S, Gravenor MB. Risk of scrapie in British sheep of different prion protein genotype. Journal of General Virology. 2004;85:2735–40. doi:10.1099/vir.0.79876‐0

[47] 47. Ikeda T, Horiuchi M, Ishiguro N, Muramatsu Y, Kai‐Uwe GD, Shinagawa M. Amino acid polymorphisms of PrP with reference to onset of scrapie in Suffolk and Corriedale sheep in Japan. Journal of General Virology. 1995;76:2577–81. doi:10.1099/0022‐1317‐76‐10‐2577

[48] 48. Groschup MH, Lacroux C, Buschmann A, Lühken G, Mathey J, Eiden M, Lugan S, Hoffmann C, Espinosa JC, Baron T, Torres JM, Erhardt G, Andreoletti O. Classic scrapie in sheep with the ARR/ARR prion genotype in Germany and France. Emerging Infectious Diseases. 2007;13(8);1201–7. doi:10.3201/eid1308.070077

[49] 49. Tranulis MA, Osland A, Bratberg B, Ulvund MJ. Prion protein gene polymorphisms in sheep with natural scrapie and healthy controls in Norway. Journal of General Virology. 1999;80:1073–77. doi:10.1099/0022‐1317‐80‐4‐1073

[50] 50. Baylis M, Goldmann W, Houston F, Cairns D, Chong A, Ross A, Smith A, Hunter N, McLean AR. Scrapie epidemic in a fully PrP‐genotyped sheep flock. The Journal of General Virology. 2002;83:2907–14. doi:10.1099/0022‐1317‐83‐11‐2907

[51] 51. Saunders GC, Cawthraw S, Mountjoy SJ, Hope J, Windl O. PrP genotypes of atypical scrapie cases in Great Britain. Journal of General Virology. 2006;87:3141–49. doi:10.1099/vir.0.81779‐0

[52] 52. François D, Elsen JM, Barillet F, Lajous D, Eychenne F, Palhière I. Breeding sheep for scrapie resistance CIHEAM. 2003;55:29–35.

[53] 53. Fediaevsky A, Calavas D, Gasqui P, Moazami‐Goudarzi K, Laurent P, Arsac J‐N, Ducrot C, Moreno C. Quantitative estimation of genetic risk for atypical scrapie in french sheep and potential consequences of the current breeding programme for resistance to scrapie on the risk of atypical scrapie. Genetics Selection Evolution 2010;42(1):1–7. doi:10.1186/1297‐9686‐42‐14

[54] 54. O'Doherty E, Healy A, Aherne M, Hanrahan JP, Weavers E, Doherty M, Roche JF, Gunn M, Sweeney T. Prion Protein (PrP) gene polymorphisms associated with natural scrapie cases and their flock‐mates in Ireland. Research in Veterinary Science. 2002;73(3):243–50. doi:10.1016/S0034‐5288(02)00073‐5

[55] 55. Acutis PL, Sbaiz L, Verburg F, Riina MV, Ru G, Moda G, Caramelli M, Bossers A. Low frequency of the scrapie resistance‐associated allele and presence of lysine‐171 allele of the prion protein gene in Italian Biellese ovine breed. The Journal of General Virology. 2004;85:3165–72. doi:10.1099/vir.0.80053‐0

[56] 56. Thorgeirsdottir S, Sigurdarson S, Thorisson HM, Georgsson G, Palsdottir A. PrP gene polymorphism and natural scrapie in Icelandic Sheep. Journal of General Virology. 1999;80:2527–34.

[57] 57. Billinis C, Psychas V, Leontides L, Spyrou V, Argyroudis S, Vlemmas I, Leontides S, Sklaviadis T, Papadopoulos O. Prion protein gene polymorphisms in healthy and scrapie‐affected sheep in Greece. The Journal of General Virology. 2004;85:547–54. doi:10.1099/vir.0.19520‐0

[58] 58. Harrington NP, O'Rourke KI, Feng Y, Rendulich J, Difruscio C, Balachandran A. Prion genotypes of scrapie‐infected Canadian Sheep 1998‐2008. Canadian Journal of Veterinary Research. 2010;74(3):228–232.

[59] 59. Gibbs CJ, Gajdusek DC. Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis). Nature. 1972;236(5341):73–74. doi:10.1038/236073a0

[60] 60. Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 1994;343(1306):405–11. doi:10.1098/rstb.1994.0036

[61] 61. Kimberlin RH, Walker CA. Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. Journal of General Virology. 1978;39(3):487–96. doi:10.1099/0022‐1317‐39‐3‐487

[62] 62. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature. 1997;389(6650):498–501. doi:10.1038/39057

[63] 63. Nathanson N, Wilesmith J, Griot C, Bovine spongiform encephalopathy (BSE): Causes and consequences of a common source epidemic. American Journal of Epidemiology. 1997;145(11):959–69. doi:10.1093/aje/kwi188

[64] 64. Comoy EE, Mikol J, Luccantoni‐Freire S, Correia E, Lescoutra‐Etchegaray N, Durand V, Dehen C, Andreoletti O, Casalone C, Richt JA, Greenlee JJ, Baron T,.Benestad SL, Brown P, Deslys J‐P. 2015. Transmission of scrapie prions to primate after an extended silent incubation period. Nature. 2015;5;11573 Scientific Reports doi:10.1038/srep11573

[65] 65. DEFRA. National Scrapie Plan for Great Britaint. 2001;1 (July):1–28.

[66] 66. Commission Decision, “Laying down minimum requirements for the establishment of breeding programmes for resistance to transmissible spongiform encephalopathies in sheep.” Official Journal 2003/100/E:L41–45.

[67] 67. EFSA. Scientific opinion on the scrapie situation in the EU after 10 years of monitoring and control in sheep and goats. EFSA Journal, 2014;12(7). doi:10.2903/j.efsa. 2014.3781

[68] 68. Hunter N, Cairns D. Scrapie‐free merino and poll dorset sheep from Australia and New Zealand have normal frequencies of scrapie‐susceptible PrP genotypes. Journal of General Virology. 1998;79:2079–82. doi:10.1099/0022‐1317‐79‐8‐2079

[69] 69. Ianella P, McManus CM, Caetano AR, Paiva SR. PRNP Haplotype and genotype frequencies in Brazilian sheep: Issues for conservation and breeding programs. Research in Veterinary Science. 2012;93(1):219–25. doi:10.1016/j.rvsc.2011.06.025

[70] 70. Gootwine E, Abdulkhaliq A, Jawasreh KIZ, Valle Zárate A. Screening for polymorphism at the prion protein (PrP) locus (PRNP) in Awassi and Assaf populations in Israel, the Palestinian Authority and Jordan. Small Ruminant Research. 2008:77(1):80–83. doi:10.1016/j.smallrumres.2008.02.008

[71] 71. Yaman Y, Soysal M, Ün C. Evaluation of the genetic resistance status to classical and atypical scrapie in Karacabey merino rams. Turkish Journal of Veterinary and Animal Sciences. 2015;39:736–40. doi:10.3906/vet‐1507‐36

[72] 72. Lühken G, Lipsky S, Peter C, Erhardt E. Prion protein polymorphisms in autochthonous European sheep breeds in respect to scrapie eradication in affected flocks. Small Ruminant Research. 2008:75(1):43–47. doi:10.1016/j.smallrumres.2007.07.010

[73] 73. Tsunoda K, Namikawa T, Sato K, Hasnath MA, Nyunt MM, Rajbandary HB, Loc CB, Zanchiv Ts, Chang H, Sun W, Dorji T. Prion protein polymorphisms and estimation of risk of scrapie in East Asian sheep. Biochemical Genetics. 2010;48(1–2): 13–25. doi:10.1007/s10528‐009‐9287‐6

[74] 74. Chelle PL. A case of trembling in the goat. Academie Veterinaire de France Bulletin. 1942;15:294–295.

[75] 75. EFSA. Scientific opinion on genetic TSE resistance in goats in all European Union. EFSA Journal. 2009;7(11):1–42. doi:10.2903/j.efsa.2009.1371

[76] 76. Wood JN, Done SH, Pritchard GC, Wooldridge MJ. Natural scrapie in goats: Case histories and clinical signs. Veterinary Record. 1992;131(4):66–68. doi:10.1136/vr.131.4.66

[77] 77. Sofianidis G, Psychas V, Billinis C, Spyrou V, Argyroudis S, Papaioannou N, Vlemmas I. Histopathological and immunohistochemical features of natural goat scrapie. Journal of Comparative Pathology. 2006;135(2–3):116–29. doi:10.1016/j.jcpa. 2006.06.004

[78] 78. Papasavva‐Stylianou P, Kleanthous M, Toumazos P, Mavrikiou P, Loucaides P. Novel polymorphisms at codons 146 and 151 in the prion protein gene of Cyprus goats, and their association with natural scrapie. Veterinary Journal. 2007;173(2):459–62. doi:10.1016/j.tvjl.2005.09.013

[79] 79. Brotherston JG, Renwick CC, Stamp JT, Zlotnik I, Pattison IH. Spread of scrapie by contact to goats and sheep. Journal of Comparative Pathology. 1968;78:9–17. doi:10.1016/0021‐9975(68)90107‐2

[80] 80. Billinis C, Panagiotidis CH, Psychas V, Argyroudis S, Nicolaou A, Leontides S, Papadopoulos O, Sklaviadis T. Prion protein gene polymorphisms in natural goat scrapie. Journal of General Virology. 2002;83;713–21. doi:10.1099/0022‐1317‐83‐3‐713

[81] 81. Toumazos P, Alley MR. Scrapie in goats in Cyprus. New Zealand Veterinary Journal 1989;37(4):160–62. doi:10.1080/00480169.1989.35595

[82] 82. Vaccari G, Panagiotidis CH, Acin C, Peletto S, Barillet F, Acutis P, Bossers A, Langeveld J, van Keulen L, Sklaviadis T, Badiola JJ, Andreéoletti O, Groschup MH, Agrimi U, Foster J, Goldmann W. State‐of‐the‐art review of goat TSE in the European Union, with special emphasis on PRNP genetics and epidemiology. Veterinary Research. 2009;40(5):48. doi:10.1051/vetres/2009031

[83] 83. Vaccari G, Di Bari MA, Morelli L, Nonno R, Chiappini B, Antonucci G, Marcon S, Esposito E, Fazzi P, Palazzini N, Troiano P, Petrella A, Di Guardo G, Agrimi U. Identification of an allelic variant of the goat PrP gene associated with resistance to scrapie. Journal of General Virology. 2006;87:1395–1402. doi:10.1099/vir.0.81485‐0

[84] 84. Acutis PL, Colussi S, Santagada G, Laurenza C, Maniaci MG, Riina MV, Peletto S, Goldmann W, Bossers A, Caramelli M, Cristoferi I, Maione S, Sacchi P, Rasero R. Genetic variability of the PRNP gene in goat breeds from northern and southern Italy. Journal of Applied Microbiology. 2008;104(6):1782–89. doi:10.1111/j.1365‐2672.2007.03703.x

[85] 85. Goldmann W, Perucchini M, Smith A, Hunter N. Genetic variability of the PrP gene in a goat herd in the UK. Veterinary Record. 2004;155:177–178.

[86] 86. Goldmann W, Ryan K, Stewart P, Parnham D, Xicohtencatl R, Fernandez N, Saunders G, Windl O, González L, Bossers A, Foster J. Caprine prion gene polymorphisms are associated with decreased incidence of classical scrapie in goat herds in the United Kingdom. Veterinary Research. 2011;42:110. doi:10.1186/1297‐9716‐42‐110

[87] 87. Serrano C, Hammouchi M, Benomar A, Lyahyai J, Ranera B, Acín C, el Hamidi M, Monzón M, Badiola JJ, Tligui N, Zaragoza P, Martín‐Burriel I. PRNP haplotype distribution in Moroccan goats. Animal Genetics. 2009;40(4):565–68. doi:10.1111/j.1365‐2052.2009.01873.x

[88] 88. Goldmann W, Martin T, Foster J, Hughes S, Smith G, Hughes K, Dawson M, Hunter N. Novel polymorphisms in the caprine PrP gene: A codon 142 mutation associated with scrapie incubation period. Journal of General Virology. 1996;77:2885–91. doi:10.1099/0022‐1317‐77‐11‐2885

[89] 89. Barillet F, Mariat D, Amigues Y, Faugeras R, Caillat H, Moazami‐Goudarzi K, Rupp R, Babilliot JM, Lacroux C, Lugan S, Schelcher F, Chartier C, Corbière F, Andréoletti O, Perrin‐Chauvineau C. Identification of seven haplotypes of the caprine PrP gene at codons 127, 142, 154, 211, 222 and 240 in French alpine and saanen breeds and their association with classical scrapie. Journal of General Virology. 2009;90:769–76. doi:10.1099/vir.0.006114‐0

[90] 90. White SN, Reynolds JO, Waldron DF. Extended scrapie incubation time in goats singly heterozygous for PRNP S146 or K222. Gene. 2012;501:49–51. doi:10.1016/j. gene.2012.03.068

[91] 91. Wopfner F, Weidenhöfer G, Schneider R, von Brunn A, Gilch S, Schwarz TF, Werner T, Schätzl HM. Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein. Journal of Molecular Biology. 1999;289(5):1163–78. doi:10.1006/jmbi.1999.2831

[92] 92. Zhou RY, Li XL, Li LH, Wang HY, Lü JG. Polymorphism of the PRNP gene in the main breeds of indigenous Chinese goats. Archives of Virology. 2008;153:979–82. doi:10.1007/s00705‐008‐0074‐1

[93] 93. Acutis PL, Bossers A, Priem J, Riina MV, Peletto S, Mazza M, Casalone C, Forloni G, Ru G, Caramelli M. Identification of prion protein gene polymorphisms in goats from Italian scrapie outbreaks. The Journal of General Virology. 2006;87:1029–33. doi:10.1099/vir.0.81440‐0

[94] 94. Acutis PL, Martucci F, D'Angelo A, Peletto S, Colussi S, Maurella C, Porcario C, Iulini B, Mazza M, Dell'atti L, Zuccon F, Corona C, Martinelli N, Casalone C, Caramelli M, Lombardi G. Resistance to classical scrapie in experimentally challenged goats carrying mutation k222 of the prion protein gene. Veterinary Research. 2012;1:43–8. doi:10.1186/1297‐9716‐43‐8

[95] 95. Goldmann W, Chong A, Foster J, Hope J, Hunter N. The shortest known prion protein gene allele occurs in goats, has only three octapeptide repeats and is non‐pathogenic. Journal of General Virology. 1998;79:3173–3176.

[96] 96. Lan XY, Zhao HY, Li ZJ, Li AM, Lei CZ, Chen H, Pan CY. A novel 28‐bp insertion–deletion polymorphism within goat PRNP gene and its association with production traits in Chinese native breeds. Genome. 2012;55(7):547–52. doi:10.1139/g2012‐040

[97] 97. Benestad SL, Sarradin P, Thu B, Schönheit J, Tranulis MA, Bratberg B. Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. The Veterinary Record. 2003;153:202–8.

[98] 98. Bruce ME, Nonno R, Foster J, Goldmann W, Di Bari M, Esposito E, Benestad SL, Hunter N, Agrimi U. Nor98‐like sheep scrapie in the United Kingdom in 1989. Veterinary Record. 2007;160:665–66. doi:10.1136/vr.160.19.665

[99] 99. Webb PR, Powell L, Denyer M, Marsh S, Weaver C, Simmons MM, Johns E, Sheehan J, Horsfield P, Lyth C, Wilson C, Long A, Cawthraw S, Saunders GC, Spencer YI. A retrospective immunohistochemical study reveals atypical scrapie has existed in the United Kingdom since at least 1987. Journal of Veterinary Diagnostic Investigation. 2009;21(6):826–29.

[100] 100. Buschmann A, Biacabe A‐G, Ziegler U, Bencsik A, Madec J‐Y, Erhardt G, Lühken G, Baron T, Groschup MH. Atypical scrapie cases in Germany and France are identified by discrepant reaction patterns in BSE rapid tests. Journal of Virological Methods 2004;117(1):27–36. doi:10.1016/j.jviromet.2003.11.017

[101] 101. Everest SJ, Thorne L, Barnicle DA, Edwards JC, Elliott H, Jackman R, Hope J. Atypical prion protein in sheep brain collected during the British scrapie‐surveillance programme. Journal of General Virology. 2006;87:471–77. doi:10.1099/vir.0.81539‐0

[102] 102. Seuberlich T, Botteron C, Benestad SL, Brünisholz H, Wyss R, Kihm U, Schwermer H, Friess M, Nicolier A, Heim D, Zurbriggen A. Atypical scrapie in a Swiss goat and implications for transmissible spongiform encephalopathy surveillance. Journal of Veterinary Diagnostic Investigation. 2007;19(1):2–8. doi:10.1177/10406387070 1900102

[103] 103. Colussi S, Vaccari G, Maurella C, Bona C, Lorenzetti R, Troiano P, Casalinuovo F, Di Sarno A, Maniaci MG, Zuccon F, Nonno R, Casalone C, Mazza M, Ru G, Caramelli M, Agrimi U, Acutis PL. Histidine at codon 154 of the prion protein gene is a risk factor for Nor98 scrapie in goats. Journal of General Virology 2008;89:3173–76. doi:10.1099/vir.0.2008/004150‐0

[104] 104. Mitchell GB, O'Rourke KI, Harrington NP, Soutyrine A, Simmons MM, Dudas S, Zhuang D, Laude H, Balachandran A. Identification of atypical scrapie in Canadian Sheep. Journal of Veterinary Diagnostic Investigation. 2010;22(3):408–11. doi:10.1177/104063871002200310

[105] 105. Kittelberger R, Chaplin MJ, Simmons MM, Ramirez‐Villaescusa A, McIntyre L, MacDiarmid SC, Hannah MJ, Jenner J, Bueno R, Bayliss D, Black H, Pigott CJ, O'Keefe JS. Atypical scrapie/Nor98 in a sheep from New Zealand. Journal of Veterinary Diagnostic Investigation. 2010:22(6):863–75. doi:10.1177/10406387100220060

[106] 106. Moum T, Olsaker I, Hopp P, Moldal T, Valheim M, Moum T, Benestad SL. Polymorphisms at codons 141 and 154 in the ovine prion protein gene are associated with scrapie Nor98 cases. Journal of General Virology. 2005;86(1):231–35. doi:10.1099/vir.0.80437‐0

[107] 107. Lühken G1, Buschmann A, Brandt H, Eiden M, Groschup MH, Erhardt G. Epidemiological and genetical differences between classical and atypical scrapie cases. Veterinary Research. 2007;38(1):65–80. doi:10.1006/geno.1993.1006

[108] 108. Moreno CR, Moazami‐Goudarzi K, Laurent P, Cazeau G, Andreoletti O, Chadi S, Elsen JM, Calavas D. Which prp haplotypes in a French sheep population are the most susceptible to atypical scrapie? Archives of Virology. 2007;152(6):1229–32. doi:10.1007/s00705‐007‐0956‐7

[109] 109. Arsac JN, Andreoletti O, Bilheude J‐M, Lacroux C, Benestad SL, Taron T. Similar Biochemical signatures and prion protein genotypes in atypical scrapie and Nor98 cases, France and Norway. Emerging Infectious Diseases. 2007;13(1):58–65. doi:10.3201/eid1301.060393

[110] 110. Wilesmith JW. Bovine Spongiform encephalopathy and related Diseases: An epidemiological overview. New Zealand Veterinary Journal. 1994;42(1):1–8. doi:10.1080/00480169.1994.35774

[111] 111. Ghani AC, Donnelly CA, Ferguson NM, Anderson RM. The transmission dynamics of BSE and vCJD. Comptes Rendus Biologies. 2002;325(1):37–47. doi:10.1016/S1631‐0691(02)01389‐6

[112] 112. WHO “World Health Organization.” World Health Organization WHO/CDS/CS (WHO Consultation on public health and animal TSEs epidemiology, risk and research requirements: 2000;1–47.

[113] 113. Will RG, Ironside JW, Zeidler M, Estibeiro, Cousens SN, Smith PG, Alperovitch A, Poser S, Pocchiari M, Hofman M. A new variant of Creutzfeldt‐Jakob disease in the UK. Lancet. 1996;347(9006):921–25. doi:10.5555/uri:pii:S0140673696914129

[114] 114. Chazot G, Broussolle E, Lapras Cl, Blättler T, Aguzzi A, Kopp N. New variant of Creutzfeldt‐Jakob disease in a 26‐year‐old French man. Lancet (London, England) 1996;347(9009):1181. doi:10.5555/uri:pii:S0140673696906388

[115] 115. Will RG. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. British Medical Bulletin. 2003;66:255–65. doi:10.1093/bmb/66.1.255

[116] 116. Foster JD, Hope J, Fraser H. Transmission of bovine spongiform encephalopathy to sheep and goats. Veterinary Record. 1993;133(14):339–341. doi:10.1136/vr.133.14.339

[117] 117. Foster JD, Parnham D, Chong A, Goldmann W, Hunter N. Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats. Veterinary Record. 2001;148:165–71. doi:10.1136/vr.148.6.165

[118] 118. Eloit M, Adjou K, Coulpier M, Fontaine JJ, Hamel R, Lilin T, Messiaen S, Andreoletti O, Baron T, Bencsik A, Biacabe AG, Beringue V, Laude H, Le Dur A, Vilotte JL, Comoy E, Deslys JP, Grassi J, Simon S, Lantier F, Sarradin P. BSE agent signatures in a goat. Veterinary Record. 2005;156(16):523–24.

[119] 119. Spiropoulos J, Lockey R, Sallis RE, Terry LA, Thorne L, Holder TM, Beck KE, Simmons MM. Isolation of prion with BSE properties from farmed goat. Emerging Infectious Diseases. 2011;17(12):2253–61.

[120] 120. Goldmann W, Hunter N, Martin T, Dawson M, Hope J. Different forms of the bovine PrP gene have five or six copies of a short, G‐C‐rich element within the protein‐coding exon. Journal of General Virology. 1991b;72:201–204.

[121] 121. Hunter N, Goldmann w, G Smith, Hope j. Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland. Veterinary Record. 1994;135(17):400–403.

[122] 122. Hills D, Comincini S, Schlaepfer J, Dolf G, Ferretti L, Williams JL. Complete genomic sequence of the bovine prion gene (PRNP) and polymorphism in its promoter region. Animal Genetics. 2001;32(4):231–232. doi:10.1046/j.1365‐2052.2001.0769a.x

[123] 123. Hills D, Schlaepfer J, Comincini S, MacLean I, Dolf G, Ferretti L, Olsaker I, Williams JL. Sequence variation in the bovine and ovine PRNP genes. Animal Genetics. 2003;34(3):183–90. doi:10.1046/j.1365‐2052.2003.00977.x

[124] 124. Clawson ML, Heaton MP, Keele JW, Smith TP, Harhay GP, Laegreid WW. Prion gene haplotypes of U.S. Cattle. BMC Genetics. 2006;7:51. doi:10.1186/1471‐2156‐7‐51

[125] 125. Vernerova K, Tothova L, Mikova A, Vodrazka P, Simek B, Hanusova L, Citek J. BSE‐associated polymorphisms in the prion protein gene : An investigation. Journal of Animal Breeding and Genetics. 2014;131(5):403–408. doi:10.1111/jbg.12090

[126] 126. Biacabe AG, Laplanche JL, Ryder S, Baron T. Distinct molecular phenotypes in bovine prion diseases. EMBO Reports. 2004;5;110–15. doi:10.1038/sj.embor.7400054

[127] 127. Casalone C, Zanusso G, Acutis P, Ferrari S, Capucci L, Tagliavini F, Monaco S, Caramelli M. Identification of a second bovine amyloidotic spongiform encephalopathy: Molecular similarities with sporadic Creutzfeldt‐Jakob disease. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(9):3065–70. doi:10.1073/pnas.0305777101

[128] 128. Heaton MP, Keele JW, Harhay GP, Richt JA, Koohmaraie M, Wheeler TL, Shackelford SD, Casas E, King DA, Sonstegard TS, Van Tassell CP, Neibergs HL, Chase CC Jr, Kalbfleisch TS, Smith TP, Clawson ML, Laegreid WW. Prevalence of the prion protein gene E211K variant in U.S. Cattle. BMC Veterinary Research. 2008;4:25. doi:10.1186/1746‐6148‐4‐25

[129] 129. Richt JA, Mark Hall S. BSE with case associated prion protein gene mutation. PLoS Pathogens. 2008;4(9):e1000156. doi:10.1371/journal.ppat.1000156

[130] 130. Nicholson EM, Brunelle BW, Richt JA, Kehrli ME Jr, Greenlee JJ. Identification of a heritable polymorphism in bovine PRNP associated with genetic transmissible spongiform encephalopathy: Evidence of heritable BSE. PloS One. 2008;3(8):e2912. doi:10.1371/journal.pone.0002912

[131] 131. Clawson ML, Richt JA, Baron T, Biacabe AG, Czub S, Heaton MP, Smith TP, Laegreid WW. Association of a bovine prion gene haplotype with atypical BSE. PloS One. 2008;3(3):e1830. doi:10.1371/journal

[132] 132. Gurgul A, Polak MP, Larska M, Słota E. PRNP and SPRN genes polymorphism in atypical bovine spongiform encephalopathy cases diagnosed in Polish Cattle. Journal of Applied Genetics. 2012;53(3):337–42. doi:10.1007/s13353‐012‐0102‐4

[133] 133. Greenlee JJ, Smith JD, West Greenlee MH, Nicholson EM. Clinical and pathologic features of H‐type bovine spongiform encephalopathy associated with e211k prion protein polymorphism. PloS One. 2012;7(6):e38678. doi:10.1371/journal.pone. 0038678

[134] 134. Anonymous. Agriculture statistics at regional level. [Internet]. 2015. http://ec.europa.eu/eurostat/statistics‐explained/index.php/Agriculture_statistics_at_ regional_level#Further_Eurostat_information [Accessed: 21.02.2015].

[135] 135. Ru G, Maurella C, Maroni Ponti A, Ingravalle F, Caramelli M. Epidemiological study of the decline of BSE in Italy. Veterinary Record. 2007;161(15):511–14. doi:10.1136/vr.161.15.511

[136] 136. Morley RS, Chen S, Rheault N. Assessment of the risk factors related to bovine spongiform encephalopathy. Revue scientifique et Technique. 2003;22(1):157–78.

[137] 137. Di Guardo G. BSE in buffaloes. The Veterinary Record. 2014;174(19):485. doi:10.1136/vr.g3177

[138] 138. Oztabak K, Ozkan E, Soysal I, Paya I, Un C. Detection of prion gene promoter and intron1 indel polymorphisms in Anatolian water buffalo (Bubalus bubalis). Journal of Animal Breeding and Genetics. 2009;126(6):463–67. doi:10.1111/j.1439‐0388.2009.00821.x

[139] 139. Imran M, Mahmood S, Babar ME, Hussain R, Yousaf MZ, Abid NB, Lone KP. PRNP gene variation in Pakistani cattle and buffaloes. Gene. 2012;505:180–85. doi:10.1016/j.gene.2012.05.038

[140] 140. Kobak P, Sablik S, Zukiewicz A, Syczewski A, Lechowicz W. Analysis of indel polymorphism of the PRNP gene in water buffalo, Bubalus bubalis. Acta Scientiarum Polonorum Zootechnica. 2014;13(1):51–56.

[141] 141. Yaman Y, Karadağ O, Ün C. Investigation of the prion protein gene (PRNP) polymorphisms in Anatolian, Murrah and crossbred water buffaloes (Bubalus bubalis). Tropical Animal Health and Production. doi:10.1007/s11250‐016‐1185‐4

[142] 142. Uchida L, Heriyanto A, Thongchai C, Hanh TT, Horiuchi M, Ishihara K, Tamura Y, Muramatsu Y. Genetic diversity in the prion protein gene (PRNP) of domestic cattle and water buffaloes in Vietnam, Indonesia and Thailand. Journal of Veterinary Medical Science. 2014;76(7):1001–8.

[143] 143. Premzl M, Sangiorgio L, Strumbo B, Marshall Graves JA, Simonic T, Gready JE. Shadoo, a new protein highly conserved from fish to mammals and with similarity to prion protein. Gene. 2003;314:89–102. doi:10.1016/S0378‐1119(03)00707‐8

[144] 144. Zhao H, Liu LL, Du SH, Wang SQ, Zhang YP. Comparative analysis of the shadoo gene between cattle and buffalo reveals significant differences. PloS One. 2012;7(10):e46601. doi:10.1371/journal.pone.0046601

[145] 145. Zhang J, Wang F, Chatterjee S. Molecular dynamics studies on the buffalo prion protein. Journal of Biomolecular Structure & Dynamics. 2015;34(4):762–777. doi:10.1080/07391102.2015.1052849

Genetic Resistance to Prion Diseases

Prion - An Overview

Abstract

Keywords

Author Information

Yalçın Yaman

Cemal Ün*

1. Introduction

2. Resistance in humans

3. Resistance in small ruminants

3.1. Resistance in sheep

Table 1.

Table 2.

Table 3.

3.2. Resistance in goats

Table 4.

3.3. Atypical scrapie in sheep and goats

Table 5.

4. Resistance in cattle

Table 6.

5. Resistance in water buffaloes

Table 7.

References

Neurobehavioral Testing in Prion Disease Studies

Your cart

Genetic Resistance to Prion Diseases

Prion - An Overview

Abstract

Keywords

Author Information

Yalçın Yaman

Cemal Ün*

1. Introduction

2. Resistance in humans

3. Resistance in small ruminants

3.1. Resistance in sheep

Table 1.

Table 2.

Table 3.

3.2. Resistance in goats

Table 4.

3.3. Atypical scrapie in sheep and goats

Table 5.

4. Resistance in cattle

Table 6.

5. Resistance in water buffaloes

Table 7.

References

Continue reading from the same book

Prion

Your cart