Genetics and polymorphism of the mouse prion gene complex: control of scrapie incubation time.

Abstract

The mouse prion protein (PrP) gene (Prn-p), which encodes the only macromolecule that has been identified in scrapie prions, is tightly linked or identical to a gene (Prn-i) that controls the duration of the scrapie incubation period in mice. Constellations of restriction fragment length polymorphisms distinguish haplotypes a to f of Prn-p. The Prn-pb allele encodes a PrP that differs in sequence from those encoded by the other haplotypes and, in inbred mouse strains, correlates with long scrapie incubation time (Westaway et al., Cell 51: 651-662, 1987). In segregating crosses of mice, we identified rare individuals with a divergent scrapie incubation time phenotype and Prn-p genotype, but progeny testing to demonstrate meiotic recombination was not possible because scrapie is a lethal disease. Crosses involving the a, d, and e haplotypes demonstrated that genes unlinked to Prn-p could modulate scrapie incubation time and that there were only two alleles of Prn-i among the mouse strains tested. All inbred strains of mice that had the Prnb haplotype were probably direct descendants of the I/LnJ progenitors. We established the linkage relationship between the prion gene complex (Prn) and other chromosome 2 genes; the gene order, proximal to distal, is B2m-II-1a-Prn-Itp-A. Recombination suppression in the B2m-Prn-p interval occurred during the crosses involved in transferring the I/LnJ Prnb complex into a C57BL/6J background. Transmission ratio distortion by Prna/Prnb heterozygous males was also observed in the same crosses. These phenomena, together with the founder effect, would favor apparent linkage disequilibrium between Prn-p and Prn-i. Therefore, transmission genetics may underestimate the number of genes in Prn.

Analysis of linkage between scrapie incubation period and the prion protein gene in mice

“…It is possible that this linkage could be explained by a BstEII restriction site difference and accompanying amino acid sequence difference at position 189 of the PrP protein of NZW mice, compared with I/LnJ and P/J mice (Westaway et al, 1987). However, in this study and previous work there have consistently been a few mice whose incubation period phenotype and PrP-linked restriction site appeared to be separable (Carlson et al, 1986(Carlson et al, , 1988. This could be explained in at least two ways.…”

“…NZW and C57BL/6 mice are believed to have many similarities in the PrP gene region (Carlson et al, 1988). Thus, it is unclear why our results comparing MA/MyJ and NZW mice showed a PrP-linked effect on the interval to death.…”

“…However, in the original report many mice died before they could be evaluated for PrP genotype (Carlson et al, 1986). More importantly, a few mice were identified in the original and subsequent reports (Carlson et al, 1988) that represented mice with potential recombinations between the incubation period and PrP genes. Therefore, we repeated the original study in order to verify the linkage between these genes.…”

“…All mice were inoculated intracerebrally with l0 s LDso of 7th mouse passage Chandler scrapie agent (Eklund et at., 1967). Scrapie incubation periods for I/LnJ, P/J, MA/MyJ and RIIIS/J mice inoculated with this agent were 255,295, 170 and 136 days respectively (Carlson et al, 1988). Linkage between the PrP-associated restriction pattern and interval to death was statistically significant (P < 0.001), based on a X 2 test for a 2 x 2 table.…”

“…In previous studies comparing MA/MyJ and C57BL/6 mice no linkage between PrP and scrapie incubation period was observed (Carlson et al, 1988). NZW and C57BL/6 mice are believed to have many similarities in the PrP gene region (Carlson et al, 1988).…”