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The amino-acid sequence of the PrP protein plays an important role in determining whether sheep are susceptible to scrapie. Although the genetics of scrapie susceptibility are now well understood, there have been few studies of the PrP gene at the population level, especially in commercially farmed sheep. Here we describe the PrP genetic profiles of the breeding stock of four UK sheep flocks, comprising nearly 650 animals in total. Two flocks had been scrapie affected for about eight years and two were scrapie free. Scrapie-resistant PrP genotypes predominated in all flocks but highly susceptible genotypes were present in each case. The distribution of PrP genotypes was similar in the scrapie-affected and scrapie-free flocks. The former, however, showed a slight but significant skew towards more susceptible genotypes despite their previous losses of susceptible sheep. Surprisingly, this skew was apparent in younger, but not older, sheep. We suggest that these patterns may occur if sheep flocks destined to become scrapie affected are predisposed by a genetic profile skewed towards susceptibility. The age structure of the scrapie-affected flocks suggests that the number of losses attributable directly or indirectly to scrapie considerably exceeds that recognized by the farmers, and also that significant losses may occur even in sheep of a moderately susceptible genotype. Similar patterns were not detected in the scrapie-free flocks, indicating that these losses are associated with scrapie infection as well as genotype.

The identification in the United Kingdom of a novel form of Creutzfeldt-Jakob disease (CJD), designated new variant Creutzfeldt-Jakob disease (nvCJD), led to the proposal that these cases might be causally linked to the occurrence of bovine spongiform encephalopathy (BSE). Since the publication of an article describing the cases and the predominantly epidemiological evidence implying a causal link (1), there has been extensive comment and debate on the strength of this data and it is perhaps timely to review the hypothesis in the light of subsequent scientific developments.

Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt–Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPScthrough a posttranslational process during which it acquires a high β-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrPSc. Transgenetic studies argue that PrPScacts as a template upon which PrPCis refolded into a nascent PrPScmolecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrPSc. While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

One of us remembers sitting in a high school biology class in 1977 being taught about scrapie, a naturally occurring disorder of sheep. The teacher had no particular interest in agriculture, but was pointing out some peculiar characteristics of this disease as a biological curiosity on a wet Friday afternoon. The prion disorders captured the imagination of a range of biologists (including that teacher) well before the epidemic of bovine spongiform encephalopathy (BSE) and the appearance of a new variant of the human prion disease, Creutzfeldt Jakob disease (CJD), in the UK, because of their extraordinary biology and the unique properties of the infectious agent. We review the results of studies leading to a convergence of evidence that the causative infectious agent, the `prion', is devoid of nucleic acid and is composed of an abnormal isoform of a host-encoded protein, the prion protein (PrP).

Some human neurodegenerative diseases, such as Kuru, Creutzfeld-Jacob, Gerstmann-Streussler-Scheinker, as well as the animal ones (scrapie in sheeps, mad cow desease, etc.), are transmitted by prion, an infectious protein PrPSc. This protein is an oligomer form of the normal cellular neuropeptide PrPC. Both proteins are encoded by the same gene PrP, which is conserved at least among mammals. Mutations within the gene cause familial forms of the same prion diseases in men. In the latter case duplications of characteristic aminoacid repeats had been discovered in the N-terminal part of PrP protein. Deletion of PrP gene in mice confers resistance to prion infection in the animal. Overexpression of the same gene induces PrPSc and prion disease in mice (see a review by Wickner et al1).

Human prion diseases occur in inherited, sporadic and acquired forms. The inherited forms are caused by coding mutations in the PrP gene; genetic susceptibility to acquired and sporadic disease is determined by a common protein polymorphism (at PrP residue 129), homozygotes being at higher risk. Recently a “new variant” of human prion disease (vCJD) has been reported in the UK and putatively linked to BSE transmission to humans. Molecular genetic analysis of PRNP coding and promotor sequence in eight vCJD cases has not to date provided evidence of genetic susceptibility factors with the exception that all are homozygous for methionine at residue 129 of PrP.

Publisher Summary The study of prions has taken several unexpected directions over the past few years. The discovery that prion diseases in humans are uniquely both genetic and infectious has greatly strengthened and extended the prion concept. To date, 20 different mutations in the human PrP gene have been found that cause the inherited prion diseases. Yet, the transmissible prion particle is composed largely, if not entirely, of PrPSC. These findings and many others argue that prions differ from all known micro-organisms as well as viruses and viroids. The knowledge accrued from the study of prion diseases may provide an effective strategy for defining the etiologies and dissecting the molecular pathogenesis of the more common neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Since people at risk for inherited prion diseases can now be identified decades before neurologic dysfunction is evident, the development of an effective therapy is imperative. The study of prion biology and diseases is a new and emerging area of biomedical investigation. While prion biology has its roots in virology, neurology, and neuropathology, its relationships to the disciplines of molecular and cell biology as well as protein chemistry have become evident only recently. Learning how prions multiply and cause disease will certainly open up new vistas in biochemistry and genetics.

The first, hypothetical explanation of the codon 200 mutation of the PrP gene in Slovak clustering CJD patients (1991) presumed a genetically increased susceptibility to exogenous (possibly zoonotic) infection. Later, worldwide-found patients with codon 200 mutation of PrP gene became generally accepted as “familial CJD”, regardless of certain non-explained observations, as an incomplete penetrance of the disease or phenotype, identical with sporadic CJD. To challenge this view a re-evaluation of data on CJD in Slovakia (annual occurrence of CJD/mill./year since 1975 varied from 1.2-0.8–2.0-1.0) has been done. A total of 104 patients, 65 with and 39 without kodon 200 mutation, have been analysed and compared from the histopathological, epidemiological and molecular biological point of view. Special attention has been paid to patients with long duration of clinical stage and age at death below 40, to a professional risk, as well as to codon 129 polymorphism. Obtained results are discussed in relation to the possible role of exogenous risk factors.

The strong links between PrP genotype and the occurrence of scrapie in sheep strengthen evidence supporting the central importance of the PrP protein in the development of transmissible spongiform encephalopathies, despite the fact that the cattle PrP gene has, so far, failed to show any association between PrP alleles and susceptibility to BSE.

Prion diseases are natural transmissible neurodegenerative disorders in humans and animals. They are characterized by the accumulation of a protease-resistant scrapie-associated prion protein (PrP Sc ) of the host-encoded cellular prion protein (PrP C ) mainly in the central nervous system. Polymorphisms in the PrP gene are linked to differences in susceptibility for prion diseases. The mechanisms underlying these effects are still unknown. Here we describe studies of the influence of sheep PrP polymorphisms on the conversion of PrP C into protease-resistant forms. In a cell-free system, sheep PrP Sc induced the conversion of sheep PrP C into protease-resistant PrP (PrP-res) similar or identical to PrP Sc . Polymorphisms present in either PrP C or PrP Sc had dramatic effects on the cell-free conversion efficiencies. The PrP variant associated with a high susceptibility to scrapie and short survival times of scrapie-affected sheep was efficiently converted into PrP-res. The wild-type PrP variant associated with a neutral effect on susceptibility and intermediate survival times was converted with intermediate efficiency. The PrP variant associated with scrapie resistance and long survival times was poorly converted. Thus the in vitro conversion characteristics of the sheep PrP variants reflect their linkage with scrapie susceptibility and survival times of scrapie-affected sheep. The modulating effect of the polymorphisms in PrP C and PrP Sc on the cell-free conversion characteristics suggests that, besides the species barrier, polymorphism barriers play a significant role in the transmissibility of prion diseases.

Ladogana et al. analyzed the available data on 4,441 cases of CJD provided from an international study. The overall annual mortality rate for sporadic CJD was 1.39 per million, with similar figures in all participating countries. Mortality rates differed for genetic, iatrogenic, and variant CJD. see page 1586 ![][1] Ladogana et al. sequenced the PRNP gene in 643 cases with suspected human transmissible spongiform encephalopathies (TSE) and found that 130 cases carried pathogenic mutations. About 60% of them had no relatives with TSE and had clinical and laboratory findings comparable to sporadic Creutzfeldt–Jakob disease. Genetic TSE patients would have been misclassified without PRNP gene analysis. see page 1592 Dufouil et al. evaluated the association of cholesterol levels, lipid-lowering agent (LLA) intake, and APOE genotype with dementia prevalence in a population-based study of 9,294 subjects. LLA intake was … [1]: /embed/graphic-1.gif

Prion diseases include kuru, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS) of humans, as well as scrapie and bovine spongiform encephalopathy (BSE) of animals. For many years, the prion dis-eases were thought to be caused by viruses, despite intriguing evidence to the contrary (Alper et al. 1966, 1967, 1978). The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited or acquired by infection, is that they involve the aberrant metabolism of the prion protein (PrP; Prusiner 1991). In many cases, the cellular prion protein (PrPC) is converted into the scrapie isoform (PrPSc) by a post-translational process which involves a conformational change. Often, the human prion diseases are transmissible to experimental animals (Gajdusek et al. 1966; Gibbs et al. 1968; Masters et al. 1981a; Tateishi et al. 1992) and all of the inherited prion diseases segregate with PrP gene mutations (Dlouhy et al. 1992; Gabizon et al. 1993; Hsiao et al. 1989a; Petersen et al. 1992; Poulter et al. 1992).

Studies with Tg mice have contributed a wealth of new knowledge about the synthesis of prion particles and the pathogenesis of both the genetic and infectious forms of the prion diseases. Transgenetic studies argue persuasively that the 'species barrier' is due to differences in PrP gene sequences among mammals.

Background The transmissible spongiform encephalopathies (TSEs) comprise a group of fatal degenerative neurological diseases in humans and other mammals. After infection, the cellular prion protein isoform PrPC is converted to the pathological PrPSC scrapie isoform. The continued conversion of PrPC to PrPSC requires de novo endogenous PrP synthesis for disease progression. The human prion protein gene (PRNP) promoter was therefore investigated to identify regulatory elements that could serve as targets for therapeutic intervention. Findings The human prion protein gene (PRNP) promoter from position -1593 to +134 relative to the putative transcriptional start site (+1) was analyzed by transient transfection in HeLa cells. Deletions from the 5' end between positions -1593 and -232 yielded little change in activity. A further 5' deletion at position -90 resulted in a decline in activity to a level of about 30% of the full-length value. DNase I footprinting of the region between positions -259 and +2 identified two adjacent protected domains designated as prpA (-116 to -143) and prpB (-147 to -186). Internal deletions combined with mobility shift electrophoresis and methylation interference assays indicated the presence of sequence specific nuclear factor complexes that bind to the prpA and prpB domains and activate expression from the human PRNP promoter in an additive fashion. Conclusion Results from transient transfection, DNase I footprinting, mobility shift electrophoresis, and methylation interference experiments suggest that two DNase I protected domains designated as prpA and prpB are binding sites for as yet unidentified regulatory factors that independently activate expression from the PRNP promoter.

A group of neurological diseases, which includes scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, is caused by prion agents which appear to be comprised solely of an abnormal variant of a cellular protein, PrP. Infectious agents which contain no genetic material pose a conundrum for molecular biologists. Theoretical analysis of the gene encoding PrP has suggested a possible mechanism of replication for this proteinaceous infectious agent. The putative mechanism involves frame-shifting during translation of the PrP gene. The normal and abnormal forms of PrP are predicted to have different amino acid sequences.

Background Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that affect several mammalian species. At least three factors related to the host prion protein are known to modulate susceptibility or resistance to a TSE: amino acid sequence, atypical number of octapeptide repeats, and expression level. These factors have been extensively studied in breeds of Bos taurus cattle in relation to classical bovine spongiform encephalopathy (BSE). However, little is currently known about these factors in Bos indicus purebred or B. indicus × B. taurus composite cattle. The goal of our study was to establish the frequency of markers associated with enhanced susceptibility or resistance to classical BSE in B. indicus purebred and composite cattle. Results No novel or TSE-associated PRNP-encoded amino acid polymorphisms were observed for B. indicus purebred and composite cattle, and all had the typical number of octapeptide repeats. However, differences were observed in the frequencies of the 23-bp and 12-bp insertion/deletion (indel) polymorphisms associated with two bovine PRNP transcription regulatory sites. Compared to B. taurus, B. indicus purebred and composite cattle had a significantly lower frequency of 23-bp insertion alleles and homozygous genotypes. Conversely, B. indicus purebred cattle had a significantly higher frequency of 12-bp insertion alleles and homozygous genotypes in relation to both B. taurus and composite cattle. The origin of these disparities can be attributed to a significantly different haplotype structure within each species. Conclusion The frequencies of the 23-bp and 12-bp indels were significantly different between B. indicus and B. taurus cattle. No other known or potential risk factors were detected for the B. indicus purebred and composite cattle. To date, no consensus exists regarding which bovine PRNP indel region is more influential with respect to classical BSE. Should one particular indel region and associated genotypes prove more influential with respect to the incidence of classical BSE, differences regarding overall susceptibility and resistance for B. indicus and B. taurus cattle may be elucidated.

International audience; Scrapie, bovine spongiform encephalopathy (BSE), and chronic wasting disease (CWD) are prion diseases in ruminants with considerable impact on animal health and welfare. They can also pose a risk to human health and control is therefore an important issue. Prion protein (PrP) genetics may be used to control and eventually eradicate animal prion diseases. The PrP gene in sheep and other representatives of the order Artiodactyles has many polymorphisms of which several are crucial determinants of susceptibility to prion diseases, also known as transmissible spongiform encephalopathies (TSE). This review will present the current understanding of PrP genetics in ruminants highlighting similarity and difference between the species in the context of TSE.

Discovery of mutations of the PrnP gene without typical plaque formation and the characterization of two prion receptors led us to postulate a new class of prion-related disease: ‘loss of function’.

Originally described by Lugaresi et al. in 1986 (ref. 1), fatal familial insomnia (FFI) is a rare inherited neurological disease characterized by the subacute progression of intractable insomnia and other autonomic abnormalities, cerebellar and pyramidal signs, myoclonus and dementia; neuropathologically, the major feature is severe neuronal loss with associated gliosis in the ventral and mediodorsal thalamic nuclei. The disease has been related to the group of spongiform encephalopathies by virtue of the presence of low levels of proteinase-resistant amyloid protein (PrPres) in the brain, and of a pathogenic single-allele mutation at codon 178 of the PRNP gene that encodes PrPres (refs 2, 5). Here we report the successful transmission of the disease to experimental animals, placing FFI within the group of infectious cerebral amyloidoses.

Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). As the other sporadic or infectious prion disease forms, they are almost all characterized by the accumulation in the brain of an abnormal misfolded form of the patient's PrP. Brain extracts can often transmit the disease once inoculated in a recipient animal. Inherited prion diseases with Creutzfeldt-Jakob disease (CJD) phenotype are autosomal forms, although sporadic cases have been reported. We report three novel mutations of the PRNP gene in unrelated patients with clinical and histopathologic features of CJD. The three mutations were missense: c635G>A (E196K), c656G>A (V203I) and c680G>C (E211Q). Familial history of neurologic disorders was evidenced for patients carrying the E196K and E211Q mutations. E196K would be predicted to have more severe effects on protein stability than V203I and E211Q. These mutations expand the spectrum of mutations in PRNP and reduce the proportion of CJD patients in whom genetic alterations have not been found. Hum Mutat 15:482, 2000. © 2000 Wiley-Liss, Inc.

We report the course of a French cohort of patients treated with growth hormone purified from human hypophyses (hGH) contaminated with the Creutzfeldt-Jakob disease (CJD) agent. 51 of the 54 confirmed probable cases of CJD in this cohort have been studied by methods that include allele-specific oligonucleotide hybridisation and sequencing of the open reading frame of the PRNP gene. The distribution of genotype at codon 129 is shown in the figure. In the Met/Met and Val/Val groups, the number of cases peaked in 1992, 8 years after growth-hormone treatment. In the Met/Val group (six cases) the earliest was identified in 1994, 5 years after the first patients in the RESEARCH LETTERS

The invention includes an artificial PrP gene, a transgenic animal containing a Prp gene of a heterologous animal, and a hybrid non-human animal with an ablated endogenous prion protein gene. Also disclosed are methods of assaying for the presence of prion particles in a sample by inoculating the claimed transgenic animals and observing the inoculated animals for symptoms associated with prion diseases.

Antoine et al. [1] and Neufeld et al. [2] reported features of a demyelinating peripheral neuropathy in cases of Creutzfeldt-Jakob disease (CJD) associated with a mutation at codon 200 of the prion protein gene. We document a further case of CJD presenting with peripheral neuropathy. In our patient, sequencing the PrP gene revealed no mutations and this case was an example of sporadic CJD. The patient was a 63-year-old man who was first seen on March 6, 1991. He first noticed slight numbness in his toes and fingers in October 1990, and by Christmas 1990, after a long drive, his feet became somewhat numb to the instep bilaterally and pain was noticed at night. In late January 1991, he noticed slight dizziness when he moved suddenly, but this …

Transgenic (Tg) mice expressing human (Hu) and chimeric prion protein (PrP) genes were inoculated with brain extracts from humans with inherited or sporadic prion disease to investigate the mechanism by which PrP c is transformed into PrP Sc . Although Tg(HuPrP) mice expressed high levels of HuPrP c , they were resistant to human prions. They became susceptible to human prions upon ablation of the mouse (Mo) PrP gene. In contrast, mice expressing low levels of the chimeric transgene were susceptible to human prionsand registered only a modest decrease in incubation times upon MoPrP gene disruption. These and other findings argue that a species-specific macromolecule, provisionally designated protein X, participates in prion formation. While the results demonstrate that PrP Sc binds to PrP c in a region delimited by codons 96 to 167, they also suggest that PrP c binds protein X through residues near the C-terminus. Protein X might function as a molecular chaperone in the formation of PrP Sc .

Transmissible spongiform encephalopathies are a group of neural degenerative diseases that may be infectious, sporadic, or hereditary and are associated with an abnormally folded prion protein. Unfortunately at the current time it is not at all clear what the normal structure of the prion protein actually is or how it is toxic to cells. Extensive research on prion diseases has led to a dramatic increase in understanding of the pathogenesis of prion disorders, which will hopefully lead to the development of effective treatments. The inability to detect the disease in blood using current technology has made screening difficult. While fortunately there has been a decline in the number of clinical cases of transmissible variant CJD, evidence indicates that very long incubation periods can occur in humans so there may be a long slow, gradual epidemic. In particular, clinical cases in genotypes other than those homozygous for methionine at codon 129 of PRNP have not yet occurred, but such cases might be expected to have longer incubation periods and show differences in pathology to those seen to date. proportion of infected animals develop sub-clinical disease. Moreover, results from a large prevalence study in humans show that several cases test positive but do not develop clinical disease. It is possible therefore that further cases of secondary transmission could occur by iatrogenic spread, which could result in vCJD persisting in the UK at low levels for many years, highlighting the importance of continued vigilance.

Prion diseases, or transmissible spongiform encephalopathies (TSEs), include bovine spongiform encephalopathy (BSE), 1 and sporadic, familiar, and variant Creutzfeldt-Jakob disease (CJD). So far, 41 deaths in the U K have been attributed to variant CJD 2 which may represent transmission of BSE to human beingsY It may seem paradoxical to discuss genetics in relation to prion diseases; after all, the prion--here defined as the enigmatic agent that causes transmissible spongiform encephalopathies--is a paradigm of non-genetic pathology. An overwhelming body of evidence agrees that the prion consists solely of a modified conformer of a normal host protein, termed PrP c. The protein-only hypothesis, originally put forward by Griffith, 6 says that prion infectivity is identical to PrP s°, an abnormal form of the cellular protein PrP c. Replication occurs by PrP s° recruiting PrP c and converting it into further PrP s°. The newly formed PrP s¢ will join the conversion cycle and lead to a chain reaction of events that results in an ever-faster accumulation of PrP s°. This hypothesis gained widespread recognition and acceptance after Stanley B Prusiner purified the pathological protein (which he termed prpsc) 7 and Charles Weissmann cloned the Prnp gene that encodes PrP sc as well as its normal cellular counterpart, p r p c y Even more momentum was achieved when Weissmann showed that genetic ablation of Prnp protects mice from experimental scrapie on exposure to prions, '° as predicted by the protein-only hypothesis. Today, we know that the prion principle underlies several biological phenomena, some of which do not necessarily result in brain disease. Most notably, the propagation of certain properties of yeast, which had been unexplained for 20 years, ~ can be conveniently accounted for by a "yeast prion" hypothesis32 Because yeast prions are not harmful to their infected hosts, and in some cases may even be advantageous, it is attractive to speculate that recruitment of structural traits by protein-protein interactions, besides underlying human prion diseases, may actually represent a fundamental principle of biology, the prevalence of which may be much greater than thus far recognised. Many variants of the protein-only hypothesis have been formulated, three of which are the most hotly debated (figure 1). Prusiner has been proposing a "templatedirected refolding" model, which postulates that a physical interaction between PrP c and PrP ~° is a precondition to the structural changes that underlie the pathogenetic conversion of PrP c. Some genetic evidence suggests the existence of a third partner protein, tentatively dubbed protein X, which may act as a molecular chaperon and facilitate misfolding of prpc? 3 Gajdusek and Lansbury and their colleagues ~4"15 have, instead, speculated that PrP c and PrP s~ exist in a

The prion hypothesis states that the partially protease-resistant and detergent-insoluble prion protein (PrP(Sc)) is identical with the infectious agent, and lacks any detectable nucleic acids. Since the latter discovery, transgenic mice have contributed many important insights to the field of prion biology. The prion protein (PrP(C)) is encoded by the Prnp gene, and disruption of Prnp leads to resistance to infection by prions. Ectopic expression of PrP(C) in PrP(C)-knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrP(C)-knockout mice, and transgenic mice overexpressing PrP(C), allowed selective reconstitution experiments aimed at expressing PrP(C) in neurografts or in specific populations of hemato- and lymphopoietic cells. The latter studies helped elucidate some of the mechanisms of prion spread and disease pathogenesis.

The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP?

The polymorphism of prion protein (PrP) amino acids in codons 136 (A/V), 154 (R/H); and 171 (Q/R/H) was established. Reproductive performance of mother sheep was evaluated analysing the fertility coefficient and litter size, i.e. the number of born and reared lambs. The studies included mothers of synthetic lines BCP - 111 sheep and SCP - 104 sheep born in 2001-2007. In the examined ovine PRNP gene, the following four alleles were identified: ARR, AHQ, ARQ, and VRQ, with the absence of the ARH allele. The highest frequency was determined for the ARR (49.8%) and ARQ (45.8%) alleles. In the studied sheep population, the occurrence of seven different genotypes was reported. It was found that 71.6% of the animals had the genotypes ARR/ARR, ARR/ARQ, and ARR/AHQ, which are regarded as the most resistant to scrapie, while 7.9% of the population had ARR/VRQ-bearing genotypes (low resistance) or ARQ/VRQ ones (high susceptibility to scrapie). The analysis of the obtained results indicates that the PRNP genotype does not affect reproduction efficiency of mothers, or their offspring growth. It was concluded that flock elimination of ewes of genotypes with high and very high susceptibility to scrapie will not reduce the reproduction parameters of ewes or growth of their lambs.

Lansbury and Caughey state in their Primer on prion proteins [1xSee all References[1] “Mice lacking the PrP gene, first produced by Charles Weissmann and colleagues, are viable, but have altered neuronal function and develop neurological abnormalities later in life.” This statement is misleading.The PrP-knockout mice produced in our laboratory [2xNormal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Bueler, H, Fischer, M, Lang, Y, Bluethmann, H, Lipp, HP, DeArmond, SJ et al. Nature. 1992; 356: 577–582Crossref | PubMed | Scopus (1045)See all References[2] do not show neurological abnormalities at any time and we have never reported such an effect. Moreover, no structural neuronal abnormalities were found in an independent line of PrP-knockout mice generated by Manson et al. [3x129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Manson, JC, Clarke, AR, Hooper, ML, Aitchinson, L, McConnell, I, and Hope, J. Mol Neurobiol. 1994; 8: 121–127Crossref | PubMed | Scopus (393)See all References[3].The phenomenon referred to by Lansbury and Caughey was observed only by Sakaguchi et al. [4xLoss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Sakaguchi, S, Katamine, S, Nishida, N, Moriuchi, R, Shigematsu, K, Sugimoto, T et al. Nature. 1996; 380: 528–531Crossref | PubMed | Scopus (380)See all References[4] in a line of mice in which not only the PrP coding region but also part of the large intron was deleted. It is not possible to attribute the observed phenotype to ablation of PrP because correction of the phenotype through introduction of a PrP-expressing cDNA has not been carried out. Electrophysiological changes were reported [[5]xRescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Whittington, MA, Sidle, KCL, Gowland, I, Meads, J, Hill, AF, Pulman, MA et al. Nature Genet. 1995; 9: 197–201Crossref | PubMed | Scopus (119)See all References, [6]xPrP gene dosage and long term potentiation. Manson, JC, Hope, J, Clark, AR, Johnston, A, Black, C, and Macleod, N. Neurodegeneration. 1995; 4: 113–115Crossref | PubMedSee all References] for two different lines of PrP-null mice, ours and those of Manson et al., but these were not reflected in neurological deficits.

Scrapie is a fatal neurodegenerative disorder of sheep and goats caused by post-translational conformational change in the host-encoded prion protein (PrPC). Susceptibility or resistance to scrapie has been associated with the presence of polymorphisms in the prion protein (PrP) gene. In the present study, we analyzed the PrP gene sequence to determine the frequency of polymorphisms in 56 sheep (28 each from Damani and Hashtnagri breeds) and 56 goats (28 each from Kamori and Local Hairy breeds). A total of 7 amino acid polymorphisms were detected in the PrP gene for sheep and 4 for goats. These amino acid polymorphisms were combined in 13 alleles and 15 genotypes in sheep and 5 alleles and 6 genotypes in goats. The overall frequency of the most sheep scrapie-resistant polymorphism (Q171R) was calculated to be 0.107. The most scrapie-susceptible polymorphism (A136V) was not detected in any of the studied sheep. The overall frequency of scrapie-associated polymorphism (H143R) in goats was found to be 0.152. Along with already known amino acid polymorphisms, two novel polymorphisms were also detected for each of sheep (Q171N and T191I) and goats (G22C and P63L). However, the overall frequency of these polymorphisms was extremely low.

Inherited Prion diseases are characterized by mutations in the PRNP gene predispose to disease by causing the expression of abnormal PrP protein. We report a 58-year-old Chinese female with mutation in codon 188 (T188K) of the PRNP gene, while the codon 129 was a methionine homozygous genotype. The patient displayed 4-year long slowly progressive sleeping disturbance and rapid exacerbation of neurological status after other neurological manifestations appeared. Cerebral spinal fluid 14-3-3 protein was positive.