Infertility due to lack of healthy prion protein

[Kathy]

I had mentioned in another post somewhere here, that sheep owners in the UK, have been stating the breeds of sheep picked by the authorities to be supposedly more resistant to scrapie, are in fact less fertile. Some did not believe this claim. Here is proof from a study done in Portugal:

Anim Reprod Sci. 2008 Oct 11.

Doppel gene polymorphisms in Portuguese sheep breeds: Insights on ram fertility.

Pereira RM, Mesquita P, Batista M, Baptista MC, Barbas JP, Pimenta J, Santos IC, Marques MR, Vasques MI, Silva Pereira M, Santos Silva F, Oliveira Sousa MC, Fontes CM, Horta AE, Prates JA, Marques CC.
L-INIA, Quinta da Fonte Boa, 2005-048 Vale de Santarém, Portugal.

Transgenic knockout of the gene encoding the prion-like protein Doppel leads to male infertility in mice. The precise role of Doppel in male fertility is still unclear, but sperm from Doppel-deficient mice appear to be unable to undergo the normal acrosome reaction necessary to penetrate the zona pellucida of the oocyte. The objective of this study was to characterize Doppel (Prnd) gene polymorphisms in eight Portuguese sheep breeds and to determine a possible relationship between these polymorphisms and ram fertility. Ovine genomic DNA of 364 animals of different breeds (Bordaleira entre Douro e Minho, Churra Badana, Churra Galega Mirandesa, Churra Mondegueira, Merino da Beira Baixa, Merino Branco, Saloia and Serra da Estrela) were analysed by multiple restriction fragment-single-strand conformation polymorphism (MRF-SSCP). This analysis revealed a synonymous substitution G-->A in codon 26 of Prnd gene. Churra Galega Mirandesa and Saloia breeds were more polymorphic (P=0.005 and P=0.04, respectively) than the overall population, while Serra da Estrela and Merino Branco animals were less polymorphic (P=0.007 and P=0.04). No polymorphism was found in Churra Mondegueira breed. Semen from 11 rams of Churra Galega Mirandesa breed (7 homozygous wildtype GG and 4 heterozygous GA) routinely used in the Portuguese Animal Germoplasm Bank was collected and frozen for fertility tests. A classification function was estimated, using data from post-swim-up semen motility and concentration and Day 6 embryo production rate, allowing the identification of the Doppel homozygous GG genotype with 86.7% of accuracy. This preliminary study detected the presence of only one polymorphism in codon 26 of Prnd gene in the Portuguese sheep breeds. In the polymorphic Churra Galega Mirandesa breed, GG genotype could be characterized through a model using three fertility traits, suggesting a relationship with male reproduction. Any future research should investigate not only AA genotype and its influence on ram fertility but also the possible consequences of the European Community selection program to eradicate Scrapie on the Prnd genotypes and indirectly on sheep breed's viability and preservation.

PMID: 19028030

[grassfarmer]

Very interesting Kathy but it doesn't in any way prove your false claims about the UK sheep industry. The first point is that the Portugese sheep breeds are genetically closer to goats than northern European sheep. The difference between them would be similar to the difference between bos taurus and bos indicus cattle so the Portugese study you have can not be assumed to apply to UK sheep.

Furthermore I would like to correct the false information you are spreading - the "breeds of sheep picked by the authorities to be supposedly more resistant to scrapie, are in fact less fertile" The authorities in the UK did not pick scrapie resistant breeds of sheep and tell people to use them as you imply. There was a general move to scrapie testing in all breeds of pure bred sheep in the UK post BSE, done with Government, veterinary and breeder co-operation.I know of no-one who has switched breeds of sheep because of their scrapie status - and I know thousands of UK sheep breeders. Similarly there have been no winners and losers on a breed basis with regard to scrapie positive/negative status - they have tested virtually the same incidence across all breeds.

[Kathy]

Sorry if my words offend, I am passing this information on from the Small Landholders Association in UK, where there were some comments by some who have switched to the government recommended breeds. These folks were concerned because they did not find them to be as reliable as their prior breeds. The problem can exist without it being widespread. We can assume that if some tried to switch to the more resistant rams - that they went back to their old breeds and continued on.

There is a direct correlation between a healthy functioning prion protein and "fertility" as well as other forms of cell differentiation.

[grassfarmer]

But there were/are no "government recommended breeds" so the scenario you outline is not plausible.

[grassfarmer]

Kathy, you might be interested to read the study available at:
http://jas.fass.org/cgi/content/full/84/6/1317

I quote from their conclusion " The results of this study indicate no evidence of an association between PrP genotypes and reproductive and growth traits. It is unlikely that selection for scrapie resistance will have an effect on the reproductive or performance traits studied in the INRA 401 breed."

[Kathy]

There are alot of studies out their we can reference. The fact that some DO reference an effect on fertility should cause concern.

Healthy issues often result from the lack of function of a mechanism.

EMBO J. 2002 Jul 15;21(14):3652-8.

Absence of the prion protein homologue Doppel causes male sterility.

Behrens A, Genoud N, Naumann H, Rülicke T, Janett F, Heppner FL, Ledermann B, Aguzzi A.
Institute of Neuropathology, UniversitätsSpital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.

The agent that causes prion diseases is thought to be identical with PrP(Sc), a conformer of the normal prion protein PrP(C). PrP(C)-deficient mice do not exhibit major pathologies, perhaps because they express a protein termed Dpl, which shares significant biochemical and structural homology with PrP(C). To investigate the physiological function of Dpl, we generated mice harbouring a homozygous disruption of the Prnd gene that encodes Dpl. Dpl deficiency did not interfere with embryonic and postnatal development, but resulted in male sterility. Dpl protein was expressed at late stages of spermiogenesis, and spermatids of Dpl mutants were reduced in numbers, immobile, malformed and unable to fertilize oocytes in vitro. Mechanical dissection of the zona pellucida partially restored in vitro fertilization. We conclude that Dpl regulates male fertility by controlling several aspects of male gametogenesis and sperm-egg interaction. PMID: 12110578


http://www.ramshornstudio.com/blackface_breeders_guild.htm

[this site, has some information on topic, and includes comments about the UK: "An eradication scheme has begun in the UK based on PrP gene susceptibility. It aims to replace scrapie-susceptible PrP alleles with more resistant ones, thereby controlling and eventually eliminating the disease from the national flock.":

"There has never been a case of natural occurring Scrapie in a Scottish Blackface Sheep. In a controlled study in the UK goats and Blackface where infected by researchers but there is not one documented case of naturally spread scrapie in a Blackface raised in the USA or the UK. Scrapie, an invariably fatal disease of sheep and goats, is a transmissible spongiform encephalopathy (TSE). The putative infectious agent is the host-encoded prion protein, PrP. The development of scrapie is closely linked to polymorphisms in the host PrP gene. The pathogenesis of most TSEs involves conversion of normal, cellular PrP into a protease-resistant, pathogenic isoform called PrPSc. The conversion to PrPSc involves change in secondary structure; it is impacts on these structural changes that may link polymorphisms to disease. Within the structured C-terminal part of PrP polymorphisms have been reported at 15 and 10 codons of the sheep and goat PrP genes respectively. Three polymorphisms in sheep are acutely linked to the occurrence of scrapie: A136V, R154H and Q171R / H. These generate five commonly observed alleles: ARQ, ARR, AHQ, ARH and VRQ. ARR and AHQ are associated with resistance; ARQ, ARH and VRQ are associated with susceptibility. There are subtle effects of specific allele pairings (genotypes). Generally, more susceptible genotypes have younger ages at death from scrapie. Different strains of scrapie occur which may attack genotypes differently. Different sheep breeds vary in the assortment of the five alleles that they predominantly encode. The reason for this variation is not known. Furthermore, certain genotypes may be susceptible to scrapie in some breeds and resistant in others. The explanation is not known, but may relate to different scrapie strains circulating in different breeds, or there may be effects of other genes which modulate the effect of PrP. There is no treatment, although the disease was eradicated from Australia and New Zealand by compulsory slaughter of imported sheep and flockmates shortly after release from quarantine. After the disease first appeared in the USA (in 1947), the Scrapie Eradication Program was established. This involved identification of affected animals and destruction of all sheep in the flock as well as other exposed flocks. This procedure was modified in 1983 to destroy mainly bloodline animals because of the strong familial occurrence of the disease. The current program in the USA is based on active, passive, and slaughter surveillance with removal of genetically susceptible sheep from flocks in which scrapie is detected. An eradication scheme has begun in the UK based on PrP gene susceptibility. It aims to replace scrapie-susceptible PrP alleles with more resistant ones, thereby controlling and eventually eliminating the disease from the national flock. In the USA the Suffolk and Hampshire present most cases of Scrapie and the Scottish Blackface none. For this reason it would be honest to relate to potential customers that Scottish Blackface meat is very safe to consume both in the USA and UK."