title: Polymorphisms at codons 108 and 189 in murine PrP play distinct roles in the control of scrapie incubation time.
abstract: Susceptibility to transmissible spongiform encephalopathies (TSEs) is associated strongly with PrP polymorphisms in humans, sheep and rodents. In mice, scrapie incubation time is controlled by polymorphisms at PrP codons 108 (leucine or phenylalanine) and 189 (threonine or valine), but the precise role of each polymorphism in the control of disease is unknown. The L108F and T189V polymorphisms are present in distinct structural regions of PrP and thus provide an excellent model with which to investigate the role of PrP structure and gene variation in TSEs. Two unique lines of transgenic mice, in which 108F and 189V have been targeted separately into the endogenous murine Prnp(a) gene, have been produced. TSE inoculation of inbred lines of mice expressing all allelic combinations at codons 108 and 189 has revealed a complex relationship between PrP allele and incubation time. It has been established that both codons 108 and 189 control TSE incubation time, and that each polymorphism plays a distinct role in the disease process. Comparison of ME7 incubation times in mouse lines that are heterozygous at both codons has also identified a previously unrecognized intramolecular interaction between PrP codons 108 and 189.
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: Rona M
authors.initials: RM
authors.lastname: Barron
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: Herbert
authors.initials: H
authors.lastname: Baybutt
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Tuzi
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: James
authors.initials: J
authors.lastname: McCormack
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: Declan
authors.initials: D
authors.lastname: King
authors.affiliation: Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Moore
authors.affiliation: Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Melton
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Manson
mesh_terms: D000818:Animals; D003062:Codon / Q000235:genetics*; D004198:Disease Susceptibility; D051379:Mice; D011110:Polymorphism, Genetic; D011328:Prions / Q000235:genetics*; D012608:Scrapie / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D012756:Sheep; D013997:Time Factors
chemical_list: D003062:Codon; D011328:Prions