Familial Human Prion Diseases

The familial prion diseases are inherited in an autosomal dominant manner and account for 10-15% of all human prion disease. They include familial CJD (fCJD), GSS, and fatal familial insomnia (FFI) (reviewed by Gambetti et al., 2003 and by Kong et al., 2003). The familial prion diseases are caused by pathogenic mutations in the PRNP coding sequence. To date, these include 24 mis-sense mutations that result in amino 

ppio2L-i29M jg jjjg jjjQgj common GSS genotype and is the first reported PRNP mutation linked to human prion dis- 

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Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

The prion diseases are a closely related group of neuro-degenerative conditions which affect both humans and animals. They have previously been described as the subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and the human prion diseases, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and kuru. Prion diseases are... 

Fig. 3. Classification of human prion diseases. Sporadic the transformation from PrPc (circle) to PrPSc (square) occurs without apparent cause. Familial a point mutation ( ) is thought to facilitate the transformation. Infectious the transformation arises via PrPSc which acts as a template. The kinetic equations are defined by Eigen (1996). The infectious form includes kuru, iatrogenic CJD (iCJD), variant CJD (vCJD first reported in 1996), bovine spongiform encephalopathy (BSE first reported in 1985), and scrapie. In the nucleation-dependent model, monomeric PrPc and PrPSc are in chemical equilibrium.

The immune system plays a central role in the pathogenesis of prion infection. In the acquired human prion diseases, it is the initial site of agent replication prior to entry into the nervous system but the immune system does not appear to be essential in the pathogenesis of the familial and sporadic human prion diseases. Followdng peripheral exposure to the prion agent, the immune system can amplify prion infection but, interestingly, the adaptive immune response does not play a role in the clearance of the prion agent. 

Known human prion diseases are Creutzfeldt-Jacob disease (CJD), Gerstmann-Straussler-Schienker syndrome (GSS) and fatal familial insomnia (FFI). GSS and FFI are inherited, whereas CJD may be inherited, sporadic or infectious. Another infectious form of CJD (iatrogenic CJD) arises from inadequately sterilized surgical instruments, dura mater grafts, and from human growth hormone isolated from cadavers. Kuru is a classical example of an infectious human prion disease transmitted by the ritual cannibalism of human brains, this disease was formerly common in the Fore tribe of New Guinea. 

Prion diseases may be genetic or infectious. Nineteen mutations of the PrP gene are associated with inherited human prion disease, all distinguishable by their phenotypes, e.g. patients with Val-129 on the mutant allele develop familial CJD, whereas those with Met-129 develop FFI. The ability of prion diseases to cross species barriers depends, at least in part, on the structural similarity between the respective PrP amino acid sequences. 

Creutzfeldt-Jakob disease (CJD) the most common prion disease of humans and can have a sporadic, familial or acquired etiology. 

Prion diseases are traditionally grouped according to their route of acquisition, as sporadic, familial, or infectious diseases. While sporadic disease variants predominate in humans, no such prion disease has yet been formally identified in animals. 

One explanation that has been proposed for the differences in occurrence of human and animal prion diseases is age-distribution. The farm animal population at highest risk for development of sporadic or familial prion disease is the elderly segment, which is normally quite small in production animals. The likelihood of discovery is further reduced by low disease incidence and challenging diagnostics. Thus, large-scale surveillance programs, with particular scrutiny of the populations at risk, have proved vital in the discovery of atypical ruminant prion diseases, as detailed in this chapter. 

Zhang YB, Swietnicki W, Zagorski MG, Surewicz WK, Sonnichsen FD (2000) Solution structure of the E200K variant of human prion protein implications for the mechanism of pathogenesis in familial prion diseases. J Biol Chem 275 33650... 

The NMR spectroscopists and other modelers have explored the possible structural basis for the familial prion diseases. The premise is that inherited prion diseases are due to destabilization of PrP on mutation, which facilitates PrP = production. The known human disease causing mutations (Fig. 1) have been mapped onto the extended human NMR... 

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