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| The EMBO Journal
(1999) 18, 6855–6864, doi:10.1093/emboj/18.23.6855 |
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| A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy |
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| Jean C. Manson1, Elizabeth Jamieson2, Herbert Baybutt1, Nadia L. Tuzi1, Rona Barron1, Irene McConnell1, Robert Somerville1, James Ironside3, Robert Will3, Man-Sun Sy4, David W. Melton2, James Hope5 and Christopher Bostock5 |
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1 BBSRC Neuropathogenesis Unit, Institute for Animal Health, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK 2 Institute of Cell and Molecular Biology, Edinburgh University, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK 3 CJD Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh, UK 4 Case Western Reserve University School of Medicine, Cleveland, OH, USA 5 Institute for Animal Health, Compton Laboratory, Newbury, Berkshire RG20 7NN, UK To whom correspondence should be addressed Jean C. Manson, jean.manson@bbsrc.ac.uk Received 20 July 1999; Revised 8 October 1999; Accepted 8 October 1999. |
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| Abstract |
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| A mutation equivalent to P102L in the human PrP gene, associated with Gerstmann–Straussler syndrome (GSS), has been introduced into the murine PrP gene by gene targeting. Mice homozygous for this mutation (101LL) showed no spontaneous transmissible spongiform encephalopathy (TSE) disease, but had incubation times dramatically different from wild-type mice following inoculation with different TSE sources. Inoculation with GSS produced disease in 101LL mice in 288 days. Disease was transmitted from these mice to both wild-type (226 days) and 101LL mice (148 days). In contrast, 101LL mice infected with ME7 had prolonged incubation times (338 days) compared with wild-type mice (161 days). The 101L mutation does not, therefore, produce any spontaneous genetic disease in mice but significantly alters the incubation time of TSE infection. Additionally, a rapid TSE transmission was demonstrated despite extremely low levels of disease-associated PrP. |
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| Keywords: gene targeting, prion diseases, PrP mutations, spontaneous prion disease, transmissible spongiform encephalopathies |
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