One of the major reasons for the numerous gene targeting experiments undertaken in the last few years has been to investigate gene function. The transmissible spongiform 192encephalopathies (TSE) are slow neurological disorders leading to neuronal degeneration in humans and animals. 1 Point mutations of the human prion protein gene can lead to familial forms of prion diseases, such as Creuzfeldt-Jakob’s disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI). 2–4 Scrapies and bovine spongiform encephalitis occur naturally in sheep, goats, and bovines and can be experimentally transmitted to mice and hamsters (reviewed in reference 1). Also the inherited prion diseases, e.g., FFI, have recently been transmitted to mice. 5 Moreover, mice with an amino acid change homologous to the mutation in humans, develop scrapie-like disease. 6 The gene which encodes for the prion protein (PrP) has been assigned to the human chromosome 20 7 and to the corresponding mouse chromosome 2. 8