Creutzfeldt-Jakob Disease (CJD) with a Mutation at Codon 148 of Prion Protein Gene

Abstract

Creutzfeldt-Jakob disease (CJD), the most common human prion disease, includes sporadic (s) and familial (f) forms. Regardless of etiology, both forms are thought to share the pathogenic mechanism whereby the cellular prion protein (PrP(C)) converts into its pathogenic isoform (PrP(Sc)). While PrP(C) conversion is thought to be random in sCJD, conversion in fCJD is facilitated by the congenital presence of mutated PrP. Differences in PrP genotype (PRNP) and in conversion circumstances lead to PrP(Sc) with distinct characteristics that elicit different disease phenotypes. Here, we describe a case of fCJD with a substitution of histidine (H) for arginine (R) at codon 148 (R148H) and heterozygosity of the methionine/valine (M/V) polymorphic codon 129, with the 129M allele coupled with the mutation. The disease phenotype and all major characteristics of PrP(Sc) of fCJD(R148H) were virtually indistinguishable from those of sCJDMV2, which has features different from those of any other sCJD. Therefore, despite the differences in etiology, PRNP, and conversion process, the two forms of PrP(Sc) had similar characteristics. Furthermore, comparison of fCJD(R148H) with a recently reported case carrying R148H and homozygosity at codon 129 suggests that codon 129 coupled with the mutation as well as that located on the normal allele can modify major phenotypic and PrP(Sc) features of fCJD(R148H).

Acid-induced Molten Globule State of a Prion Protein

“…Interestingly, it has been suggested that critical interactions in H1 are involved in the pathogenic conversion mechanism (34), which has been further verified experimentally (35). An R148H mutation that disrupts the Asp 144 -Arg 148 hydrogen bond causes symptoms similar to the sporadic Creutzfeldt-Jakob disease MV2 subtype (36). In addition, a E196K mutation is a phenotype of inherited prion disease, which typically presents a rapidly progressive dementia and ataxia (37).…”

Insoluble Aggregates and Protease-resistant Conformers of Prion Protein in Uninfected Human Brains

“…Two-dimensional gel electrophoresis was performed as described by the supplier using the PROTEIN IEF cell (BioRad) (27,32). Samples denatured by boiling in SDS sample buffer were incubated with reducing buffer (8 M urea, 2% CHAPS, 5 mM tributylphosphine, 20 mM Tris, pH 8.0) for 1 h at room temperature and then incubated with 200 mM iodoacetamide for 1 h. Proteins were precipitated with a 5-fold volume of pre-chilled methanol at Ϫ20°C for 2 h and centrifuged at 16,000 ϫ g for 20 min at 4°C.…”

Global transcriptional profiling of the postmortem brain of a patient with G114V genetic Creutzfeldt-Jakob disease

“…fCJD accounts for approximately 10-15% of all CJD cases, characterized by the genetic changes of PrP (2). To date, 56 different mutations, including residue substitutions, insertions and deletions, have been reported (3). For instance, proline to leucine mutation at the 102nd position (P102L) causes Gerstmann-StrausslerScheinker syndrome (GSS) characterized by the impairment of cerebellum (4).…”