Prion diseases inherited

Pathogenic mutations in the prion protein gene cause inherited prion disease 793... 

Collinge, J. et al. Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases. Am. J. Hum. Genet. 49 1351-1354,1991. 

A large number of point mutations have been described. Several show marked ethnogeographic clustering related to the occurrence of a mutation in a founder whose descendants migrated and increased in frequency in different geographical regions in accordance with the history of human populations. Only the common mutations that illustrate some of the key genetic aspects of inherited prion diseases are described here. 

Baker HE, Poulter M, Crow TJ et al (1991) Aminoacid polymorphism in human prion protein and age at death in inherited prion disease. Lancet 337 1286... 

Tateishi J, Kitamoto T (1995) Inherited prion diseases and transmission to rodents. Brain Pathol 5 53-59... 

The central role of PrPc in the pathogenesis of prion diseases was demonstrated in transgenic mice with a targeted disruption of the PrP gene PrP0/0 mice are resistant to prion diseases and do not propagate infectious prions [32]. Moreover, inherited prion diseases in humans are causally linked to mutations in Pmp (reviewed in [22, 33]). 

Kong Q, Surewicz WK, Petersen RB et al (2004) Inherited prion diseases. In Prusiner SB (ed) Prion biology and diseases. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY... 

Peoc h K, Manivet P, Beaudry P, Attane F, Besson G, Hannequin D, Delasnerie-Laupretre N, Laplanche J-L (2000) Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene PRNP in inherited prion diseases with Creutzfeldt-Jakob disease phenotype. Hum Mutat 15 482... 

Fig. 6. Influence of amino acid replacements associated with inherited human TSEs on the thermodynamic stability of recombinant murine PrP( 121-231) at pH 7.0 and 22°C (Liemann and Glockshuber, 1999). The upper panel indicates the amino acid replacements in mature human PrP that are linked with inherited prion diseases in humans. The lower panel shows the difference between the free energy of unfolding of wild-type murine PrP(121-231) and the corresponding variant (AAG). The difference is defined such that a destabilization relative to the wild-type leads to positive values of AAG. The free energy of folding of wild-type murine PrP (121-231) at pH 7.0 and 22°C is -29.7 + 1.0 kj moPh The maximum error of the measured AAG values is + 2.6 kj moPh Variants of PrP( 121-231) that could not be expressed in a soluble form in the E. coli periplasm and formed periplasmic inclusion bodies are marked by asterisks. AAG for the replacement E200Khas also been determined for human PrP(90-231) with guani-dinium chloride as denaturant, and has a value of 4.1 + 2.6 kJ moP (Swietnicki et al., 1998, dashed bar frame).

Finally, an important feature of prions in familial TSEs may he the stoichiometry and suhunit composition of PrP = isolated from affected individuals. Analysis of the allelic origin of the protease-resistant PrP oligomer isolated from patients with inherited prion diseases yielded different results for individual mutations. In the case of the mutations at positions 102,178,198, 200, and 217, only the mutant PrP forms pro-tease-resistant PrP = (Kitamoto et al, 1991 Tagliavini et al, 1994 Bar-banti etal, 1996 Gabizon etal, 1996 Chen etal, 1997). In contrast, the mutation at position 210 (Silvestrini et al, 1997) and also the insertion... 

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... 

Transmission of PrP fragment sizes from two different subtypes of inherited prion disease to transgenic mice expressing a chimeric human mouse PrP has also been reported (Telling et al., 1996). These... 

Prion and scrapie diseases are linked with the conformational transition of normally monomeric a-helical cellular prion protein, PrP, to a B-sheet-rich pathogenic form, PrP , which is prone to aggregation. A similar conformational transition of the normal cellular form of a-helical amyloid peptide (aAP (1-40)) into the disease-specific largely B-sheet form of amyloid peptide (BAP (1-40)) occurs in Alzheimer s disease, which results in amyloid deposits (Monaco et al., 2006). So far more than 19 different mutations in the human PrP gene have been linked with inherited prion diseases (Monaco et al., 2006). However, the molecular event triggering the spontaneous conversion of wild-type and... 

These transmissible diseases, with insoluble protein as the infectious agent, would seem to have originated as mutations, and within this context they became inherited prion diseases. Creutzfeld-Jakob disease, GSS, and FFI number among those now recognized as inherited prion diseases in humans. 

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