Genetics of prion diseases

Abstract

Prion diseases are transmissible, fatal neurodegenerative diseases that include scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease (CJD) in human. The prion protein gene (PRNP) is the major genetic determinant of susceptibility, however, several studies now suggest that other genes are also important. Two recent genome wide association studies in human have identified four new loci of interest: ZBTB38-RASA2 in UK CJD cases and MTMR7 and NPAS2 in variant CJD. Complementary studies in mouse have used complex crosses to identify new modifiers such as Cpne8 and provided supporting evidence for previously implicated genes (Rarb and Stmn2). Expression profiling has identified new candidates, including Hspa13, which reduces incubation time in a transgenic model.

Figure 1

From modifier gene discovery to functional validation. Current strategies for prion disease susceptibility gene discovery include both human and mouse studies. These include human GWAS case–control studies and complementary QTL and GWAS studies in advanced mouse crosses. GWAS results can be displayed as a Manhattan plot as shown here with highly significant hits shown for PRNP SNPs. Expression profiling of key tissues for example comparing short (blue) and long (red) incubation time mice has also revealed new pathways and candidates. Next generation sequencing of patients can now be used to identify high risk alleles at novel genes to generate an allelic mutation series as shown here for PRNP. Options for functional validation of candidate genes include both in vitro (scrapie cell assay) and in vivo approaches (mouse models). GWAS – genome-wide association studies; CJD – Creutzfeldt–Jakob disease; QTL – quantitative trait loci; SNP – single nucleotide polymorphism.

Figure 2

PrP mutations and polymorphisms. A schematic representation of full length human PrP is shown with the cleaved signal sequences shown in grey and the octapeptide repeat region in pink. Disease associated mutations are shown in red and non-synonymous non-pathogenic genetic variants in green. OPRD – octapeptide repeat deletion; OPRI – octapeptide repeat insertion.