[Molecular genetics of familial and sporadic forms of human prion diseases]

Prion diseases, also known as transmissible subacute spongiform encephalopathies (TSSE), are rare neurodegenerative disorders of both humans and animals. Their biochemical hallmark is an accumulation in the brain of an abnormal form of the host-encoded prion protein (PrP). This pathological accumulation could result from a protein conformational change under the influence of unknown factors. The normal function of PrP is unknown. The abnormal form is thought to induce neurodegeneration when experimentally or accidentally introduced in recipient hosts. Such a possibility would explain the transmissible character of these diseases illustrated in humans by iatrogenic contamination. Considerable attention has been focused on the host PrP gene and its relation with the genetic susceptibility of humans and animals. Mutations in PRNP, the gene which encodes PrP in humans, are present in 17% of the patients and might be causative. In patients without any PRNP mutation, a coding polymorphism (129 Met/Val) defines a predisposing factor. Important progress in the molecular genetics of TSSE in both humans and animals have been performed for few years and point out that the development of different forms of these diseases, experimental, iatrogenic or spontaneous, are strongly dependent on the primary structure of the host PrP.