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Polymorphisms at codons 108 and 189 in murine PrP play distinct roles in the control of scrapie incubation time

James McCormack^1,

Richard C. Moore^2,

¹ Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK
² Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh, UK
³ Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK

Correspondence
Rona M. Barron
rona.barron{at}bbsrc.ac.uk

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.

Published online ahead of print on 5 January 2005 as DOI 10.1099/vir.0.80525-0.

A supplementary figure showing ME7 and 301V incubation times in mice expressing codon 108 and 189 polymorphisms is available in JGV Online.

Present address: Department for Environment, Food and Rural Affairs (DEFRA), Veterinary Research Division, TSE Research Unit, Dean Stanley Street, London, UK.

Present address: Department of Genetics and Genomics, Roslin Institute, Edinburgh, UK.

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