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Published on: October 3, 2012
Distinct prion proteins in short and long scrapie incubation period mice
D Westaway1, P A Goodman, C A Mirenda
1Department of Neurology, University of California, San Francisco 94143.
Abstract:
The Prn-i gene, controlling scrapie incubation period, is linked to or congruent with the murine prion protein (PrP) gene, Prn-p. In prototypic mouse strains with long (l/Ln) and short (NZW) incubation periods, Prn-p transcription is initiated at similar multiple sites. The predicted NZW and l/Ln PrP proteins differ at codons 108 and 189. Codon 189, highly conserved in mammals, lies within a polymorphic BstEll site that is retained in 17 mouse strains known to have short or intermediate incubation times, but is absent in l/Ln and two other inbred mice with long incubation times. Codon 108 in mice with short or intermediate incubation times encodes Leu; in mice with long incubation times it encodes Phe. The correlation of PrP sequence with length of scrapie incubation period suggests, but does not formally prove, congruency between Prn-p and Prn-i.
Insights
The prion protein gene (Prn-p) sequence correlates with scrapie incubation periods in mice. Variations at codons 108 and 189 in Prn-p influence incubation time, suggesting its link to the Prn-i gene.
Area of Science:
- Genetics
- Neuroscience
- Immunology
Background:
- The gene controlling scrapie incubation period (Prn-i) is closely associated with the mouse prion protein gene (Prn-p).
- Prn-p gene transcription initiation sites are similar in mouse strains with differing scrapie incubation periods.
Purpose of the Study:
- To investigate the relationship between Prn-p gene sequence variations and scrapie incubation periods in mice.
- To determine if Prn-p sequence polymorphisms correlate with the incubation time of scrapie.
Main Methods:
- Comparative analysis of Prn-p gene sequences in mouse strains with known long (l/Ln) and short (NZW) scrapie incubation periods.
- Examination of Prn-p protein differences at specific codons (108 and 189).
- Analysis of a polymorphic BstEll restriction site associated with codon 189 across various mouse strains.
Main Results:
- Mouse strains with short or intermediate scrapie incubation times possess a BstEll site at codon 189, absent in long incubation strains.
- Codon 108 encodes Leucine in short/intermediate incubation mice and Phenylalanine in long incubation mice.
- Prion protein (PrP) sequence variations at codons 108 and 189 are strongly correlated with scrapie incubation period length.
Conclusions:
- The sequence of the Prn-p gene is a significant factor influencing scrapie incubation periods in mice.
- The findings strongly suggest, though do not definitively prove, that Prn-p and Prn-i are congruent.
- PrP sequence polymorphisms are key determinants of susceptibility and incubation time in prion diseases.
