International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Lloyd SE 1, Maytham ELG 1, Thompson S 1, Mott R 2, Fisher EMC 1, Collinge J 1

1 MRC Prion Unit, London, United Kingdom, 2 The Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Prion diseases are fatal neurodegenerative disorders of both humans and animals which include scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. They are characterised by prolonged incubation periods which in mice can vary from 100-500 days.  The main genetic determinant of incubation time is the prion gene, Prnp, where allele a (Leu 108, Thr 189)  and allele b (Phe 108, Val 189) are associated with short and long incubation times respectively.  Large scale linkage studies have now successfully identified additional modifier loci on at least eight different chromosomes. Because the regions of linkage identified in these crosses were broad (10-30cM), we are now employing a number of different approaches for fine mapping and candidate gene identification. One strategy is to use a heterogeneous stock of mice. These are derived from the semi-random mating of eight inbred lines of mice (A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J and LP/J) over multiple generations. Approximately 1000 mice at generation 37 were inoculated intracerebrally with RML/scrapie and incubation times were recorded. 400 animals representing both extremes of the incubation time distribution were genotyped at 1cM intervals in regions previously reported to contain quantitative trait loci.  HAPPY linkage analysis of these data successfully identified regions on chromosomes 11 and 15 representing loci of 1-2cM.  These intervals are small enough for individual candidate gene analysis which we are investigating through the use of quantitative RT-PCR and sequencing to identify the molecular basis of the variation.

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