Human prion diseases are fatal neurodegenerative disorders that are characterized by spongiform changes, astrogliosis, and the accumulation of an abnormal prion protein (PrPSc). Approximately 10%-15% of human prion diseases are familial variants that are caused by pathogenic mutations in the prion protein gene (PRNP). Point mutations or the insertions of one or more copies of a 24 bp repeat are associated with familial human prion diseases including familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. These mutations vary significantly in frequency between countries. Here, we compare the frequency of PRNP mutations between European countries and East Asians. Associations between single nucleotide polymorphisms (SNPs) of several candidate genes including PRNP and CJD have been reported. The SNP of PRNP at codon 129 has been shown to be associated with sporadic, iatrogenic, and variant CJD. The SNPs of several genes other than PRNP have been showed contradictory results. Case-control studies and genome-wide association studies have also been performed to identify candidate genes correlated with variant and/or sporadic CJD. This review provides a general overview of the genetic mutations and polymorphisms that have been analyzed in association with human prion diseases to date.Graphical Abstract

Human prion protein gene (PRNP) is considered an important gene in determining the incidence of human transmissible spongiform encephalopathies or prion diseases. Polymorphisms of PRNP at codon 129 in Europeans and codon 219 in Japanese may play an important role in the susceptibility to sporadic Creutzfeldt-Jakob disease (CJD); data regarding codon 129 in the Japanese population have led to divergent interpretations. In order to determine which, if any, of the PRNP genotypes in Korean people are associated with sporadic CJD, we examined the genotype and allelic distributions of human PRNP polymorphisms in 150 patients with sporadic CJD. All Korean sporadic CJD patients were Met/Met at codon 129, Glu/Glu at codon 219 and undeleted at the octarepeat region of PRNP. Our study showed significant differences in genotype frequency of PRNP at codon 129 (chi 2=8.8998, P=0.0117) or 219 (chi 2=12.6945, P=0.0004) between sporadic CJD and normal controls. Furthermore, the genotype frequency of the heterozygotes for codons 129 and/or 219 showed a significant difference between the normal population and sporadic CJD patients (chi 2=21.0780, P<0.0001).

The PMCA (protein misfolding cyclic amplification) technique has been shown to drive the amplification of misfolded prion protein by PrP(Sc) seeds during several cycles of incubation-sonication. Here, we report that cyclic amplification of normal hamster brain homogenates treated with a number of transition metals (manganese [Mn], copper [Cu], and iron [Fe]) leads to conversion of PrP(C) into protease-resistant PrP(res). The efficiency of PrP(res) formation and the glycoforms induced by Mn were different from those obtained by Cu and Fe. Previous results have shown higher Mn and lower Cu levels in the affinity-purified PrP(Sc) from the brain of prion diseases compared with normal hamster brain homogenates. We focused on Mn because we observed higher levels of Mn in whole brain, mitochondria, and scrapie-associated fibril-enriched fractions from the brains of animals with prion disease. In the presence of minute quantities of Mn-induced PrP(res) template with a large amount of PrP(C), PrP(res) amplification is observed. A metal chelater, EDTA reverses the effect of Mn on PrP(res) amplification, suggesting that Mn may play a role in the formation of PrP(res). It has been proposed that metal-catalyzed oxidation of PrP leads to the oxidation of amino acids and extensive aggregation of oxidized PrP. Carboxyl acids such as deoxycholic acid (DA) are oxidized molecules produced by 3' oxidation pathway. In in vitro studies, the potent effect of Mn on PrP(res) amplification is augmented by DA in a dose-dependent manner. On the basis of the evidence of the elevated Mn levels in scrapie-associated fibril (SAF)-enriched preparations from the brains of animals with prion disease, Mn-loaded PrP and oxidized molecules such as carboxyl acids may contribute to the formation of the scrapie isoform of PrP in prion diseases.

Human prion protein gene (PRNP) has been considered to be involved in the susceptibility of humans to prion diseases. Polymorphisms of methionine (Met)/ valine (Val) at codon 129 and of glutamic acid (Glu)/ lysine (Lys) at codon 219 are thought to play an important role in susceptibility to sporadic, iatrogenic and variant Creutzfeldt-Jakob disease (CJD). Although the genotype distribution of polymorphisms in PRNP open reading frame (ORF) has been reported in many European populations, among Asian groups, it has been reported only in the Japanese population. We examined the PRNP polymorphisms in 529 healthy Koreans. We observed that genotype frequencies at codon 129 was 94.33% Met/Met, 5.48% Met/Val, and 0.19% Val/Val with an allele frequency of 0.971:0.029 Met:Val, and that genotype frequencies at codon 219 was 92.06% Glu/ Glu, 7.94% Glu/Lys, and 0% Lys/Lys with an allele frequency of 0.96:0.04 Glu:Lys. The frequencies of the Glu/Glu genotype (v 2 =10.075, P=0.0015) and of the Glu allele (v 2 =9.486, P=0.0021) at codon 219 were significantly higher in the Korean population than the Japanese population. In addition, the genotype frequency of heterozygotes (12.7%) at codons 129 or/and 219 was significantly lower in Koreans than in people from Great Britain (v 2 =89.52, P<0.0001). The deletion rate of one octarepeat (R2 deletion) was 0.38%, with 99.62% undeleted homozygotes and 0% deleted homozygote. To our knowledge, the R2 octarepeat deletion has never been found in people from countries other than Korea. The data of PRNP polymorphism at codon 219 suggest that Koreans may be more sensitive to sporadic CJD than the Japanese population.

Antibody to hepatitis B surface antigen (HBsAg) (anti-HBs) can exist in patients with chronic hepatitis B virus (HBV) infection. To date, little is known about the association of concurrent HBsAg and anti-HBs (concurrent HBsAg/ anti-HBs) with hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinical relevance of concurrent HBsAg/anti-HBs with preS deletion mutations and HCC in chronic HBV infection. A total of 755 patients with chronic HBV infection were included consecutively at a tertiary center. Logistic regression analysis was used to identify risk factors for HCC, and serum HBV DNA was amplified, followed by direct sequencing to detect preS deletions. The prevalence of concurrent HBsAg/anti-HBs was 6.4% (48/755) and all HBVs tested were genotype C. HCC occurred more frequently in the concurrent HBsAg/anti-HBs group than in the HBsAg only group [22.9% (11/48) vs. 7.9% (56/707), P = 0.002]. In multivariate analyses, age >40 years [odds ratio (OR), 14.712; 95% confidence interval (CI), 4.365-49.579; P < 0.001], male gender (OR 2.431; 95% CI, 1.226-4.820; P = 0.011), decompensated cirrhosis (OR, 3.642; 95% CI, 1.788-7.421; P < 0.001) and concurrent HBsAg/anti-HBs (OR, 4.336; 95% CI, 1.956-9.613; P < 0.001) were associated independently with HCC. In molecular analysis, preS deletion mutations were more frequent in the concurrent HBsAg/anti-HBs and HCC groups than in the HBsAg without HCC group (42.3% and 32.5% vs. 11.3%; P = 0.002 and 0.012, respectively). In conclusion, concurrent HBsAg/anti-HBs is associated with preS deletion mutations and may be one of the risk factors for HCC in chronic HBV infection with genotype C.