Identification of seven haplotypes of the caprine PrP gene at codons 127, 142, 154, 211, 222 and 240 in French Alpine and Saanen breeds and their association with classical scrapie

Abstract

In sheep, susceptibility to scrapie is mainly influenced by polymorphisms of the PrP gene. In goats, there are to date few data related to scrapie susceptibility association with PrP gene polymorphisms. In this study, we first investigated PrP gene polymorphisms of the French Alpine and Saanen breeds. Based on PrP gene open reading frame sequencing of artificial insemination bucks (n=404), six encoding mutations were identified at codons 127, 142, 154, 211, 222 and 240. However, only seven haplotypes could be detected: four (GIH154RQS, GIRQ211QS, GIRRK222S and GIRRQP240) derived from the wild-type allele (G127I142R154R211Q222S240) by a single-codon mutation, and two (S127IRRQP240 and GM142RRQP240) by a double-codon mutation. A case–control study was then implemented in a highly affected Alpine and Saanen breed herd (90 cases/164 controls). Mutations at codon 142 (I/M), 154 (R/H), 211 (R/Q) and 222 (Q/K) were found to induce a significant degree of protection towards natural scrapie infection. Compared with the baseline homozygote wild-type genotype I142R154R211Q222/IRRQ goats, the odds of scrapie cases in IRQ211Q/IRRQ and IRRK222/IRRQ heterozygous animals were significantly lower [odds ratio (OR)=0.133, P<0.0001; and OR=0.048, P<0.0001, respectively]. The heterozygote M142RRQ/IRRQ genotype was only protective (OR=0.243, P=0.0186) in goats also PP240 homozygous at codon 240. However, mutated allele frequencies in French Alpine and Saanen breeds were low (0.5–18.5 %), which prevent us from assessing the influence of all the possible genotypes in natural exposure conditions.

High prevalence of scrapie in a dairy goat herd: tissue distribution of disease-associated PrP and effect ofPRNPgenotype and age

“…The genotype frequencies at codon 142 in these 200 goats were 40.0% II 142 , 46.5.0% IM 142 and 13.5% MM 142 (I, isoleucine; M, methionine). 1 Jeffrey and Spiropoulos, unpublished data.…”

“…This is well established for sheep, but less well examined for goats [11]. The most common amino acid polymorphisms in British goat breeds are at codons 127 (glycine or serine), 142 (isoleucine or methionine), 143 (histidine or arginine) and 240 (proline or serine), and an association of polymorphisms at codons 142 and 143 with susceptibility and incubation period has been reported [1,2,10]. A comprehensive review of the goat PNRP gene polymorphisms and their association with disease has recently been published [31].…”

Genetic Resistance to Prion Diseases

“…Encoding of serine instead of glycine at codon 127 has decreased the probability of clinical manifestation of the disease [86]. Isoleucine-methionine dimorphism at codon 142 has found to be associated both experimental [88] and natural infection [86,89]; furthermore, it is reported that [89] the presence of methionine-isoleucine as heterozygous at codon 142 has been provided resistance only in proline-proline homozygous animal at codon 240. Encoding of arginine at codon 143 has provided limited protection to natural scrapie [80].…”

“…While the presence of asparagine instead of Serine or Aspartic acid at codon 146 has been found to be related to susceptibility to natural infection [78], it also has reported that the presence of Serine as heterozygous at the same codon has associated with the extended incubation period in oral challenging [90]. According to the results of various studies, arginine-histidine dimorphism at codon 154 has provided limited resistance [78,80,83,89]. The presence of glutamine/arginine as heterozygous at codon 211 has been found to Abbreviations of the amino acids: A, alanine; D, aspartic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan.…”

“…The presence of glutamine/arginine as heterozygous at codon 211 has been found to Abbreviations of the amino acids: A, alanine; D, aspartic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan. be related to lower susceptibility [89], and the presence of lysine at codon 222 has been associated with resistance to both natural [83,89,93] and oral [90] or intracerebral challenging [94].…”