Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease

Abstract

The human prion diseases, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS), are neurodegenerative diseases that are unique in being both infectious and genetic. Transmission of both diseases and the animal spongiform encephalopathies (for example, scrapie and bovine spongiform encephalopathy) to experimental animals by intracerebral inoculation with brain homogenates is well documented. Despite their experimental transmissibility, missense and insertional mutations in the prion protein gene are associated with both GSS and familial CJD, demonstrating that the human familial cases are autosomal dominant diseases. More than 80% of CJD cases occur sporadically, however, and are not known to be associated with mutations. Here we report that 21 of 22 sporadic CJD cases and a further 19 of 23 suspected sporadic CJD cases are homozygous at the polymorphic amino-acid residue 129; 51% of the normal population are heterozygous at this site. We argue that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

“…Interpretation has been hampered by the inability to do confirmatory immunoblotting of formalin-fixed tissue and by the fact that two of the three positive specimens that could be analysed were from individuals with a PRNP codon 129 valine homozygous genotype [50]. Polymorphism at residue 129 of human PrP [encoding either methionine (M) or valine (V)] powerfully affects susceptibility to human prion diseases, with residue 129 acting to restrict the propagation of particular prion strains through conformational selection [6,51,52] and heterozygosity conferring resistance by inhibiting homologous protein-protein interactions [52][53][54]. To date, all patients with neuropathologically confirmed vCJD have been PRNP codon 129 methionine homozygotes [7,26] and have a remarkably uniform and distinct neuropathological phenotype defined by the presence of abundant florid PrP plaques [1] and the propagation of type 4 PrP Sc [2,55] in the brain.…”

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

“…Two predominant PrP sc types have been identified, based on the gel mobility of the PrP sc fragments resistant to proteinase K (PK) treatment, and they are associated with different CJD phenotypes (Cali et al, 2006;Gambetti et al, 2003;Monari et al, 1994;Petersen et al, 1994). Parallel to this, PRNP polymorphism at codon 129 (Met 129 →Val) modulates sensitivity to CJD, and methionine homozygosis is a risk factor for sporadic and variant CJD (Collinge, 1999;Ladogana et al, 2005;Palmer et al, 1991). However, conflicting results have been reported about the relationship between polymorphism at codon 129 and the pathological and clinical features of AD (Hooper and Turner, 2008;Poleggi et al, 2008) for reviews) although a systematic meta-analysis of AD genetic association studies revealed PRNP as a susceptible gene ((Bertram and Tanzi, 2008) for review).…”

Risikofaktoren der sporadischen Creutzfeldt-Jakob-Krankheit

“…Ein Einfluss des Genotyps am Codon 129 des PRNP auf die Suszeptibilität und Inkubationszeit der sCJK ist beschrieben (Palmer et al 1991). Bei CJK-Patienten, deren Erkrankung auf infektiöse menschliche Wachstumshormone (hGH) zurück-zuführen ist, wurden signifikant kürzere Inkubationszeiten bei Homozygotie als bei Heterozygotie am Codon 129 festgestellt (Aignaux et al 1999, Brandel et al 2003.…”