Prion disease genetics

Abstract

Prion diseases have stimulated intense scientific scrutiny since it was proposed that the infectious agent was devoid of nucleic acid. Despite this finding, genetics has played a key role in understanding the pathobiology and clinical aspects of prion disease through the effects of a series of polymorphisms and mutations in the prion protein gene (PRNP). The advent of variant Creutzfeldt-Jakob disease has confirmed one of the most powerful human genetic susceptibility factors, as all tested patients have an identical genotype at polymorphic codon 129 of PRNP. This review will also consider the accrued reports of inherited prion disease and attempt a genotype-phenotype correlation. The prospects for detection of novel genetic susceptibility factors using mouse models and human genetic association studies will be explored.

Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology

“…Cases of sCJD are unrelated, non-familiar, and have no apparent genetic association. They happen at any place and independent of other TSE [28]. It remains to be established in the coming years by collecting more cases whether the spontaneous disease model will be correct or whether atypical scrapie is an infectious disease like most TSE with an aetiology similar -and maybe complementary -to classical scrapie.…”

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…The D178N mutation in human PrP is involved in familial prion disease [131]. Intriguingly, the phenotype of disease is significantly altered by the common M/V polymorphism at res.…”

PrPgenetics in ruminant transmissible spongiform encephalopathies

“…- Polymorphisms of interest are G65E, Q95H, G96S, A116G, G129S, S138N, V169M, N176D, M209I, S225F, and Q226K [42,50,54,66]. Taking both deer subfamilies together the number of unique PrP proteins is 17.…”

“…From almost 1 800 alleles that have been published for mule deer and white-tailed deer at least 25% had an additional mutation. Of the 562 wapiti PrP sequences 18% carried the only known polymorphism in this species (132L) [42,53,55,66].…”

“…Sheep have one additional allele with four octapeptides (six repeats in total) [78], and goats have one additional allele with only one octapeptide (three repeats in total) [33]. It has been shown that a total number of repeats above eight is associated with increased risk to Creutzfeldt-Jakob disease, a human form of TSE [28,66]. In contrast the relevance of a repeat variation between three and seven, found in ruminants, to TSE susceptibility has not yet been fully resolved.…”