Genetics of Prion Disease

Prion diseases or transmissible spongiforrn encephalopathies (TSEs) are neurodegenerative disorders of humans and animals for which there are no effective treatments or cure. They include Creutzfeldt-Jakob disease (CJD) in humans and sheep scrapie, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in cervids. The prion protein (PrP) is central to the disease process. An abnormal form of PrP is generally considered to be the sole or principal component of the infectious agent and a multimeric isomer (PrPSc) is deposited in affected brains. Inherited prion diseases are caused by over 30 mutations in the prion protein gene (PRNP) and common polymorphisms can have a considerable affect on susceptibility and phenotype. Susceptibility and incubation time are also partly determined by other (non-PRNP) genetic modifiers. Understanding how these other genes modify prion diseases may lead to insights into biological mechanisms. Several approaches including human genome wide association studies (GWAS), mouse mapping and differential expression studies are now revealing some of these genes which include RARB (retinoic acid receptor beta), the E3 ubiquitin ligase HECTD2 and SPRN (Shadoo, shadow of prion protein gene).