PubMed Health⌕ Search

Biomedical subjects

W Goldmann

Publications and source records attributed to W Goldmann.

At least 37 records · Page 2Linked to original sources
PubMed1999

Experimentally induced bovine spongiform encephalopathy did not transmit via goat embryos.

Goats are susceptible to experimental challenge with bovine spongiform encephalopathy (BSE). This study set out to investigate whether the transmission of BSE could occur in goats following the transfer of embryos from experimentally infected donor females into uninfected recipient females. The results showed no evidence of transmissible spongiform encephalopathy disease in any of the offspring which developed from embryos from infected donors, nor indeed in any of the recipient females used as surrogate dams. In addition, there was no indication of experimental BSE spreading as either a venereal infection to males used in mating or by maternal transmission to offspring born naturally to experimentally infected donors, although numbers were small.

Animals↗
PubMed1998

The shortest known prion protein gene allele occurs in goats, has only three octapeptide repeats and is non-pathogenic.

The prion protein (PrP) gene modulates the incidence and incubation periods of transmissible spongiform encephalopathies of sheep, goats, mice and man. Here, a new caprine PrP allele encoding the shortest naturally occurring PrP protein so far described is reported. This variant contains only three instead of the usual five copies of a short peptide repeat [Pro-Gln/His-Gly-Gly-Gly-(Gly)-TrpGly-Gln] characteristic of PrP, with an additional Trp to Gly substitution in codon 102. Fifteen out of 111 genotyped goats carried the novel PrP allele and 14 survived without signs of disease for at least 4 years. One goat heterozygous for the polymorphism was challenged experimentally with SSBP/1-scrapie and succumbed after an unusually long incubation period.

Alleles↗
PubMed1997

Natural scrapie and PrP genotype: case-control studies in British sheep.

Natural scrapie in sheep is associated with polymorphisms of the PrP gene, particularly at amino acid codons 136, 154 and 171. This paper reports the results of nine scrapie case-control studies in Bleu du Maine, Herdwick, Merino x Shetland, Poll Dorset, Scottish Halfbred, Shetland, Soay, Suffolk and Swaledale sheep from British flocks affected by scrapie. In some outbreaks, scrapie was found to occur only in animals with at least one PrP allele encoding valine at codon 136 (V136), usually a relatively rare allele in healthy controls. In other outbreaks, the V136, PrP allele was either not found or was not an absolute prerequisite for scrapie to develop. Although scrapie had a strong tendency to affect sheep with PrP genotypes homozygous for glutamine at codon 171 (QQ171), these genotypes (QQ171 but varying at other codon positions) were relatively common in healthy controls. The reliable prediction of scrapie susceptibility in previously uninvestigated sheep flocks will therefore require information at least about PrP genotypes at codons 136 and 171.

Animal Husbandry↗
PubMed1997

Immunodetection of PrPSc in spleens of some scrapie-infected sheep but not BSE-infected cows.

The development of diagnostic tools for transmissible spongiform encephalopathies (TSEs) would greatly assist their study and may provide assistance in controlling the disease. The detection of an abnormal form of the host protein PrP in noncentral nervous system tissues may form the basis for diagnosis of TSEs. Using a new antibody reagent to PrP produced in chickens, PrP can be readily detected in crude tissue extracts. PrP from uninfected spleen had a lower molecular mass range than PrP from brain, suggesting a lower degree of glycosylation. A simple method for detecting the abnormal form of the protein, PrPSc, in ruminant brain and spleen has been developed. PrPSc was detected in sheep spleen extracts from a flock affected by natural scrapie and was also found in spleens from some, but not all, experimental TSE cases. In spleens from cattle with bovine spongiform encephalopathy (BSE) no PrPSc was detected. It is therefore suggested that there is differential targeting of PrPSc deposition between organs in these different types of TSE infection which, with other factors, depends on strain of infecting agent.

Animals↗
PubMed1996

Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes.

Natural scrapie in a closed flock of South Country Cheviot sheep has resulted in 45 deaths between 1986 and 1995. Of these cases, 35 sheep have been analysed for disease-linked PrP gene polymorphisms and all encode valine at codon 136 on at least one allele with 77% homozygous (VV136) and 23% valine/alanine heterozygotes (VA136). Mean survival time was 907 and 1482 days for VV136 and VA136 scrapie affected animals respectively. VV136 animals were all at great risk of disease if allowed to live long enough. However scrapie occurred only in a specific subgroup of VA136 sheep, survival advantage depending on VA136 animals being heterozygous for other polymorphisms at codons 154 or 171. The flock history has been recorded in great detail since its foundation in 1960 however there was no strong evidence for simple maternal or paternal transmission of disease other than inheritance of PrP genotype.

Animals↗
PubMed1996

Novel polymorphisms in the caprine PrP gene: a codon 142 mutation associated with scrapie incubation period.

Age at disease onset and rate of progression of transmissible spongiform encephalopathies in man, sheep and mice are modulated by the host genome, in particular by the PrP gene and its allelic forms. Analysis of the caprine PrP gene revealed several different alleles. Four PrP protein variants were found, three of which were goat specific with single amino acid changes at codons 142, 143 and 240. The fourth was identical to the most common sheep PrP protein variant (Ala136-Arg154-Gln171). The dimorphism at codon 142 (Ile --> Met) appeared to be associated with differing disease incubation periods in goats experimentally infected with isolates of bovine spongiform encephalopathy, sheep scrapie CH1641 or sheep-passaged ME7 scrapie.

Amino Acid Sequence↗
PubMed1994

Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland.

Bovine spongiform encephalopathy (BSE) is one of a family of scrapie-like diseases which affect various mammals. Polymorphisms and mutations of the PrP gene have been associated with the incidence of experimental and natural scrapie in other animals and this study of the bovine PrP gene was undertaken to discover whether there was a similar association with PrP genotype in cattle with BSE. There are two known polymorphisms of the coding region of the bovine PrP gene, a silent HindII restriction site polymorphism and a difference in the number of an octapeptide repeated sequence (either five or six copies). An analysis of 370 cattle in Scotland revealed no difference between the frequencies of these PrP genotypes in healthy cattle and cattle with BSE.

Animals↗
PubMed1994

The association of a codon 136 PrP gene variant with the occurrence of natural scrapie.

Incidence of both experimental and natural scrapie in sheep has been associated with polymorphisms of the PrP gene. In case/control studies the PrP allele which encodes valine at codon 136 (Val136) is found in 96-100% of naturally infected scrapie sheep of Shetland, Scottish Halfbred and Blue du Maine breeds. In contrast, in healthy animals from the same flocks, the most frequent allele encodes Ala136 (91-100% of sheep). However Val136 does not correlate with incidence of scrapie in two other flocks--Poll Dorsets and Suffolks--and there may therefore be breed differences in PrP genotypes affected by scrapie.

Alleles↗
PubMed1994

PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie.

Man and sheep are the two species in which spongiform encephalopathies occur naturally, and in which there are recognized genetic components that predispose an individual person or sheep to clinical disease. In both species mutations/polymorphisms in the PrP gene have been linked to the incidence of natural disease, but only in sheep is it possible to investigate by deliberate exposure to infection whether these polymorphisms are directly correlated with survival time. Cheviot sheep of different PrP genotypes were challenged with one of two isolates of scrapie or an isolate of bovine spongiform encephalopathy and the survival time and incidence of disease were monitored. Genotype analysis showed that dimorphisms in codons 136 and 171 of the ovine PrP gene correlated with control of disease incidence and modulation of incubation time. Crucially, the functional effects of these domains of PrP were shown to alternate depending on the isolate of infecting agent.

Alleles↗
PubMed1993

PrP gene and its association with spongiform encephalopathies.

The PrP or prion protein plays a key role in the pathogenesis of the transmissible spongiform encephalopathies. This 33-35 kD sialoglycoprotein is the product of a single host gene which is composed of 2 or 3 exons, a single open reading frame and a cytidine/guanidine rich promoter. The structure of the gene and the sequence of the protein are highly conserved in various mammals. Primarily, transcription of the PrP gene is found in neurons of the central and peripheral nervous system but other tissues do express PrP at least at some stages of development. Translation of the PrP mRNA and processing of the initial gene product result in a 210 amino acid protein with asparagine-linked glycosylation of the complex type which attaches itself to the outer leaflet of the plasma membrane lipid bilayer by a C-terminal glycosylinositol phospholipid. The function of this protein is unknown. Development of the transmissible spongiform encephalopathies, and increasing titre of the causative pathogen, are associated with the accumulation in and around cells of pleiomorphic aggregates of PrP which are partially resistant to proteolytic hydrolysis. These abnormal deposits of PrP, and the normal isoform, are transcribed from the same gene and so any disease-linked modification of the protein must be post-transcriptional. No disease-specific, covalent modifications of PrP have yet been found and some simple, conformational change in its secondary, tertiary (or quaternary) structure may underlie its role in these diseases. Polymorphisms in the PrP gene of different species have been associated with disease but none of these changes in primary structure appear to cause protease resistance per se. Preclinical inference of disease susceptibility can already be made using PrP genotype analysis in man and some animals but developing a cure for these diseases, whether by drug or gene therapy, will require a much greater understanding of the molecular and cell biology of this gene and its products. This article presents current views and understanding of the PrP gene.

Animals↗
PubMed1993

Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie.

PrP glycoprotein gene polymorphisms were examined in Swaledale sheep affected by natural scrapie, in healthy sheep and in Swaledales selected for low susceptibility to scrapie. The three groups differed significantly in frequencies of PrP genotypes detected by the restriction enzymes EcoRI, HindIII and BspHI, the latter being indicative of a PrP protein amino acid difference at codon 136. These frequency differences were confirmed in a single-flock study and present good evidence that scrapie susceptibility and resistance are associated with PrP gene variants in Swaledale sheep.

Age Factors↗
PubMed1992

Polymorphisms of a scrapie-associated fibril protein (PrP) gene and their association with susceptibility to experimentally induced scrapie in Cheviot sheep in the United States.

The duration of the incubation period for scrapie, a fatal transmissible neurodegenerative disorder of sheep and goats, is mainly determined by the Sip gene, which has 2 alleles (sA--susceptible and pA--resistant). A diagnostic test is not available to detect scrapie in live animals. We analyzed genomic DNA extracted from frozen sheep brains collected from Cheviot sheep of the United States that had been inoculated with the SSBP/1 scrapie inoculum. Digestion of the DNA with EcoRI or HindIII followed by the addition of a scrapie-associated fibril protein (PrP)-specific marker probe, yielded fragments of 6.8 (e1) and 4.0 (e3) kb, or 5.0 (h1) and 3.4 (h2) kb, respectively. Fragments e1 and h2 were associated with the histopathologic diagnosis of scrapie, and fragments e3 and h1 were associated with survival. A valine/alanine polymorphism within the PrP coding region that resulted in a BspHI site was further used to determine the genotype of these Cheviot sheep. Digestion of polymerase chain reaction fragments with BspHI resulted in an undigested fragment b- (0.840 kb), digested fragments b+ (0.460 and 0.380 kb), or both types of fragments. Survival time of b+/b+ homozygous sheep was significantly (P < 0.01) shorter (218 +/- 26.0 days) than survival time for b-/b- sheep (> 700 days after inoculation). Results indicated that b+ and b- are markers for the Sip sA and pA alleles, respectively. The intermediate duration of the incubation period for heterozygous sheep (b+/b-; 342.9 +/- 25.3 days) indicated that the Sip sA allele is expressed codominantly to the Sip pA allele.

Animals↗
PubMed1991

Different forms of the bovine PrP gene have five or six copies of a short, G-C-rich element within the protein-coding exon.

Current models of the virus-like agents of scrapie and bovine spongiform encephalopathy (BSE) have to take into account that structural changes in a host-encoded protein (PrP protein) exhibit an effect on the time course of these diseases and the survival time of any man or animal exposed to these pathogens. We report here the sequence of different forms of the bovine PrP gene which contain either five or six copies of a short, G-C-rich element which encodes the octapeptide Pro-His-Gly-Gly-Gly-Trp-Gly-Gln or its longer variants Pro-Gln/His-Gly-Gly-Gly-Gly-Trp-Gly-Gln. Out of 12 cattle, we found eight animals homozygous for genes with six copies of the Gly-rich peptide (6:6), while four were heterozygous (6:5). Two confirmed cases of BSE occurred in (6:6) homozygous animals.

Alleles↗
PubMed1991

Different scrapie-associated fibril proteins (PrP) are encoded by lines of sheep selected for different alleles of the Sip gene.

The incubation period of scrapie in sheep is controlled by the Sip gene which has two alleles (sA and pA). Following experimental challenge with SSBP/1 scrapie, a short incubation period is conferred by the partially dominant sA allele. Restriction fragment length polymorphisms of the scrapie-associated fibril protein (PrP) gene are associated with the Sip alleles. By sequencing the protein coding region of the PrP gene in Cheviot sheep selected for differing Sip genotypes, we have found four PrP protein variants which differ at three positions: amino acid 112 (Ala/Val), amino acid 130 (Arg/His) and amino acid 147 (Arg/Gln). The Val 112 variant can be distinguished at the DNA level by an RspXI restriction site which is not present in the Ala 112 form. Val 112 appears to be linked to a short incubation period of experimentally induced scrapie in the Cheviot sheep and therefore with the Sip sA allele. These results provide new evidence that the PrP protein may be a product of the Sip locus.

Alleles↗
PubMed1990

Two alleles of a neural protein gene linked to scrapie in sheep.

Sheep are the natural hosts of the pathogens that cause scrapie, an infectious degenerative disease of the central nervous system. Scrapie-associated fibrils [and their major protein, prion protein (PrP)] accumulate in the brains of all species affected by scrapie and related diseases. PrP is encoded by a single gene that is linked to (and may be) the major gene controlling the incubation period of the various strains of scrapie pathogens. To investigate the role of PrP in natural scrapie, we have determined its gene structure and expression in the natural host. We have isolated two sheep genomic DNA clones that encode proteins of 256 amino acids with high homology to the PrPs of other species. Sheep PrPs have an arginine/glutamine polymorphism at position 171 that may be related to the alleles of the scrapie incubation-control gene in this species.

Alleles↗