Ovine PRNP untranslated region and promoter haplotype diversity

Abstract

The diversity and possible contribution of non-coding regions of the prion protein (PrP) gene (PRNP) to transmissible spongiform encephalopathy susceptibility and PrP regulation are not fully known. This study defined ten ovine PRNP promoters and five untranslated region (UTR) haplotypes found in atypical and classical scrapie cases and healthy control sheep. A greater diversity of promoter and UTR haplotypes was observed in conjunction with the ARQ PrP allele (seven promoter and four UTR haplotypes), while it was observed that the other alleles were linked with a limited number of haplotypes, such as ARR, found to be linked to only two promoter and one UTR haplotypes. In silico analysis identified potential transcription factor binding sites that differed in the promoter haplotype variants. Furthermore, a 59 UTR internal ribosome entry site motif was identified in exon 2 and highlights a possible role for this exon in regulating PrP expression at the translational level.Scrapie is a member of the transmissible spongiform encephalopathy (TSE) family of diseases, whose natural hosts are sheep and goats. TSEs are degenerative disorders of the nervous system and are invariably fatal. Irrespective of whether these diseases are acquired, inherited or of idiopathic origin, the prion protein (PrP) plays a central role (Prusiner, 1998).The PRNP gene codes for the ovine PrP, is over 20 kb long and contains three exons separated by two introns of 2421 and 14031 bp (Lee et al., 1998). The 768 bp coding region or open reading frame (ORF) of PrP is contained entirely within exon 3. The 59 untranslated region (UTR) consists of exon 1, exon 2 and bases 1-10 of exon 3 and the 39 UTR (bases 779-4028) of exon 3 (Fig. 1).Polymorphisms within the PRNP ORF are known to be associated with susceptibility and resistance to classical and atypical scrapie in sheep (Goldmann et al., 1994;Benestad et al., 2003;Moum et al., 2005 (shortened to ARQ when omitting the 141 codon). This allele, plus those generated through the substitution of one of its amino acids, make up the six most common ovine PrP alleles, namely ARQ, VRQ, AHQ, ARR and ARH, which all have leucine at position 141, and AF 141 RQ, which has phenylalanine at this position.Other regions of PRNP could also influence susceptibility, either independently or in synergy with the coding region, and may prove beneficial in future breeding plans, particularly in rare breeds, to maximize genetic diversity in the national flock whilst maintaining scrapie resistance (Dawson et al., 2008). For example, polymorphisms in the PRNP promoter region could destroy or create a transcription factor binding site (TFBS) that in turn leads to the down-or upregulation of PrP and influences disease susceptibility or incubation period. The mechanism by which the 39 UTR region of PRNP could affect scrapie susceptibility and resistance is not known; however, Goldmann et al. (1999) demonstrated that the length of the 39 UTR in mRNA can affect PrP expression levels. In general, the 39 UTR can be involved in ...

Protective effect of the T112 PrP variant in sheep challenged with bovine spongiform encephalopathy

“…Whilst the majority of resistant sheep carry at least one TARQ allele, there are two Suffolk sheep and numerous Romney sheep that exhibit BSE resistance in the absence of the TARQ allele. Therefore, some other, as-yet-unknown factor, potentially a non-coding region of the PRNP gene (Saunders et al, 2009), must be responsible in these cases.…”

Genetic effects of PRNP gene insertion/deletion (indel) on phenotypic traits in sheep

“…Polymorphisms within the third exon of the ovine PRNP gene at codons 136 [7], 141 [8],146 [9], 154 [10], and 171 [11] are closely associated with variation in the phenotypic expression of scrapie. Other regions of PRNP, either independently or in synergy with the coding region, could also influence susceptibility [12]. With extensive and thorough studies, these pathogenic codons are filtered out by artificial selection (e.g.…”

Analysis of 3’UTR of Prnp Gene in Mammals: Possible Role of Target Sequences of miRNA for TSE Sensitivity in Bovidae and Cervidae

“…Otherwise, several studies point out that the expression level of the prion gene could modulate the onset of TSE, particularly in cattle (Sander et al, 2004(Sander et al, -2006Haase et al, 2007). The involvement of the 5' promoter region has been investigated in sheep (Saunders et al, 2009) and cattle (Xue et al, 2008) and it appears that polymorphism in this region could induce different responses to scrapie (Marcos-Carcavilla et al, 2008) and BSE (Brunelle et al, 2008). The analysis of a 23 pb insertion/deletion polymorphism in German and Swiss breed cattle revealed that the deletion is associated to a higher expression level, more frequently A Bird's-Eye View of Veterinary Medicine 524 found in cattle affected with classical BSE.…”