Polymorphisms at codons 108 and 189 in murine PrP play distinct roles in the control of scrapie incubation time.
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.
Barron
Rona M
RM
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
Baybutt
Herbert
H
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
Tuzi
Nadia L
NL
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
McCormack
James
J
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
King
Declan
D
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
Moore
Richard C
RC
Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh, UK.
Melton
David W
DW
Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Manson
Jean C
JC
Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK.
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
D003062:Codon; D011328:Prions