New ovine PrP gene haplotypes as a result of single nucleotide polymorphisms in the PrP gene promoter.

Incidence of scrapie in sheep is strongly associated with PrP gene amino acid codon variants at positions 136, 154 and 171. However, there are breed differences in disease linkage and anomalous disease patterns which cannot obviously be explained by the '3 codon' genotype. Mouse studies indicate that PrP protein levels can influence scrapie disease progression and this prompted us to study the sheep PrP gene promoter region in a search for novel polymorphisms which may influence gene expression and hence disease susceptibility. The incidence of three single nucleotide polymorphisms (SNP) at positions C/A-5354, T/C-5382 and C/G-5622 within the PrP gene promoter region was determined from Neuropathogenesis Unit (NPU) and New Zealand (NZ) Cheviot and UK and NZ Suffolk sheep. The SNP variants A-5354 and G-5622 created consensus sequences for STAT and SP1 transcription factors, respectively, and C-5382 was within Motif 1, one of four conserved motifs found within the promoter region of mammalian PrP genes. The occurrence of C/A-5354 and T/C-5384 SNP exhibited differential associations with the PrP open reading frame (ORF) variants linked to scrapie susceptibility. A significant imbalance in the incidence of the C-5354/AXQ haplotype was found in the NPU Cheviot flock. C-5382 was not found in Suffolk sheep of either UK or NZ origin. The G-5622 SNP was found at a lower incidence in Suffolk sheep compared with Cheviots. The range of transcription factor binding motif profiles in the PrP gene promoter may act to modulate PrP gene activity and warrants further large-scale study.