The Genetics of Susceptibility to Variant Creutzfeldt-Jakob Disease

Abstract

The emergence of bovine spongiform encephalopathy (BSE) in cattle and, subsequently, its transmission to humans resulting in variant Creutzfeldt-Jakob disease (vCJD) in the UK has proved to be one of the major public health scares of the century. The oral route of infection, the long incubation period, and the incredible resistance of the transmissible infectious agent to various forms of decontamination poses unique challenges. Fortunately, despite extensive exposure of the UK population to contaminated meat, the size of the vCJD epidemic that has emerged since its initial detection is relatively low (225 worldwide). An explanation for this disparity is as yet incomplete, but the development of the disease is likely influenced by a number of factors including physical properties of the infectious agent, environmental factors such as the route and amount of exposure and individual susceptibility factors. This review focuses on current knowledge of the genetic factors that undoubtedly play a major role in influencing the development of vCJD. In terms of genetic susceptibility, the best characterised is the common single nucleotide polymorphism at codon 129 of the human prion protein gene (PRNP). Moreover, several other polymorphisms and mutations have been identified that may affect susceptibility as well as other important disease characteristics such as the highly variable prion disease incubation period.

Pathologic and biochemical characterization of PrPSc from elk with PRNP polymorphisms at codon 132 after experimental infection with the chronic wasting disease agent

“…The elk PRNP codon 132 polymorphism is homologous to the human PRNP codon 129 polymorphism that encodes either methionine (M) or valine (V) [ 39 , 40 ]. In TSE-affected humans, the MM129 genotype is associated with susceptibility to kuru [ 23 ] and variant Creutzfeldt-Jakob disease (vCJD) [ 38 ]. Some studies have found that elk expressing prion protein homozygous for methionine at codon 132 (hereafter referred to as MM132 elk) are over-represented among CWD-affected elk [ 11 , 12 , 31 , 41 ], while another study concluded that elk of all 3 genotypes (MM132, LM132, LL132) show equivalent susceptibility [ 36 ].…”

DISCONTOOLS: Identifying gaps in controlling bovine spongiform encephalopathy

“…It is not yet possible to rule out that the incidence of vCJD may increase again, particularly if different genetic subgroups with longer incubation periods exist. Work in transgenic mice expressing human PrP has demonstrated that all codon 129 genotypes are potentially susceptible to infection with BSE, albeit with different incubation periods (Asante et al., ; Cassard et al., ; Padilla et al., ; Saba & Booth, ).…”

“…It is not yet possible to rule out that the incidence of vCJD may increase again, particularly if different genetic subgroups with longer incubation periods exist. Work in transgenic mice expressing human PrP has demonstrated that all codon 129 genotypes are potentially susceptible to infection with BSE, albeit with different incubation periods(Asante et al, 2002;Cassard et al, 2014;Padilla et al, 2011;Saba & Booth, 2013).Non-human primates and transgenic mouse models expressing human PrP have been shown to be permissive to infection with both C-BSE and L-BSE(Beringue et al, 2008;Kong et al, 2008; Mestre- Frances et al, 2012) although not, to date, with H-BSE, suggesting…”

Genetics of Prion Disease in Cattle

“…More specifically, this singlenucleotide polymorphism (SNP) rs1799990 at codon 129 of the PRNP gene encodes for either methionine (M = ATG) or valine (V = GTG) and is a known genetic factor that contributes to the risk of developing vCJD. 30,38 In cattle, the western blot profile of C-BSE differs from that of atypical BSE. Atypical BSE cases are designated as such due to the observable variation in molecular mass profiles.…”