Genetic Studies in Human Prion Diseases

Abstract

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

Rare E196A mutation in PRNP gene of 3 Chinese patients with Creutzfeldt-Jacob disease

“…3 Till now, more than 55 mutations in the PRNP coding sequence have been described associating with human genetic prion diseases, whose clinical manifestations and neuropathological abnormalities may vary largely depending on the various genotypes. 4 More than 60 cases of various genetic prion diseases have been identified by Chinese National CJD Surveillance Network since 2006, FFI, T188K gCJD and E200K gCJD were the most leading genetic prion diseases. 5 Here we reported 3 Chinese gCJD cases with a substitution from glutamic acid to alanine at codon 196 (E196A) by PRNP sequencing and all patients were methionine homozygous at codon 129 and glutamic acid homozygous at codon 219.…”

The associations of two SNPs in miRNA-146a and one SNP in ZBTB38-RASA2 with the disease susceptibility and the clinical features of the Chinese patients of sCJD and FFI

“…The polymorphism of codon 129 in PRNP gene is a welldocumented example, which not only affects the susceptibility of the diseases, such as sCJD and variant CJD (vCJD), but also determines the clinical phenotype of some genetic prion diseases, such as D178N/ M129M FFI and D178N/M129V gCJD. Along with the development of gene sequencing, many research groups have conducted the studies in different populations in order to address the possible relationships of various SNP polymorphisms with prion diseases in the past decade [3].…”

“…More than 50 mutations have been found in the open reading frame (ORF) of PRNP, which are directly linked with the genetic prion diseases [2]. In addition to these mutations, some polymorphisms have also been observed inside or outside the ORF of PRNP [3], particularly the polymorphisms at codon 129 and 219.…”

Rare genetic Creutzfeldt-Jakob disease with E196A mutation: a case report

“…Genetic prion diseases (gPrDs) are caused by point or insertion mutations in the prion protein (PrP) encoding gene, PRNP, which is the only gene known to be associated with gPrDs [3]. The PRNP mutation is necessary for the diagnosis of gCJD in symptomatic individuals [1].…”