Molecular genetics of familial and sporadic forms of human prion diseases

Human prion diseases, also known as transmissible subacute spongiform encephalopathies (TSE), are rare neurodegenerative conditions characterized by the accumulation of an abnormal form of prion protein (PrP) in the central nervous system. PrP is present on the surface of neurones and its precise role has not yet been determined. PrP undergoes conformation modification under the influence of unknown factors, making it resistant to cellular proteases and responsible for pathological accumulation in the neurones. The modified protein seems to be able to induce neurodegeneration in the host. This property is the basis of the transmissible nature of these diseases, of which there are very many examples of iatrogenic contamination in man. The transmissible nature of TSEs has focused attention on the role of the gene coding for PrP in determining genetic susceptibility of both humans and animals to these diseases. PRNP mutations, the human gene coding for PrP, are identified in 17% of patients and are considered to be causal factors. A particular distribution of a frequent polymorphism affecting codon 129 (Met/Val) is found in patients without these mutations. The molecular genetics of spongiform encephalopathies is a field of research for these diseases which has been particularly enhanced in recent years. Although the role of the prion protein remains unclear, combined human and animal studies have shown that the development of these diseases, whether experimental, iatrogenic or spontaneous, is highly dependant on the primary structure of the host PrP.