NR AOVY
AU Lloyd,S.E.; Thompson,S.; Mott,R.; Fisher,E.M.C.; Collinge,J.
TI Quantitative trait locus analysis of prion disease incubation time in mice
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - DG-76
PT Konferenz-Poster
AB Prion disease incubation time in mice is a quantitative trait varying 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. Significant differences in incubation times occur between inbred lines with the same Prnp alleles suggesting that other genes are contributing to the observed variation. To identify these loci we analysed an F2 intercross between two strains of mice, CAST/Ei and NZW/OlaHsd, with significantly different incubation periods when challenged intracerebrally with either RML/ scrapie prions or mouse passaged BSE. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11 and 12 for RML/scrapie and overlapping regions on chromosomes 2 and 11 for mouse passaged BSE, suggesting that these loci may act independently of prion strain. Because the regions of linkage identified in these crosses were broad (10-20cM), we are now employing a number of different approaches for fine mapping and candidate gene identification. These strategies include the generation of congenic mice and the use of a heterogeneous stock of mice to reduce the size of the regions. Approximately 1000 of these outbred mice 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 QTL. Statistical 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.
IN Lloyd et al. inokulierten mit RML-Scrapie oder einem Hausmaus-adaptierten BSE-Stamm Hausmäuse, die alle identische Prionproteine exprimierten, sich aber hinsichtlich anderer Gene unterschieden. Sie konnten die resultierenden unterschiedlichen Inkubationszeiten mit Unterschieden in bestimmten Regionen auf den Mauschromosomen 2, 11, 12 und 15 korrelieren.
AD S.E. Lloyd, S. Thompson, E.M.C. Fisher, J. Collinge, MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, London, UK; R. Mott, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
SP englisch
PO Deutschland