A novel PRNP-P105S mutation associated with atypical prion disease and a rare PrP^Sc conformation

Abstract

Objective: To define the clinicopathologic, genetic, and pathogenic prion protein (PrP^Sc) characteristics associated with a novel mutation of the prion protein gene (PRNP).

Methods: The coding segment of PRNP from the proband and family members was sequenced and the brain of the proband was histologically studied. The Western blot profile of the proteinase K (PK) resistant fraction of PrP^Sc, an approximation of its conformation, or “PrP^Sc-type,” was determined.

Results: We detected a novel mutation at codon 105 of PRNP that results in a serine (S) substitution of proline (P) (P105S), in a young woman who developed progressive aphasia, behavioral changes, dementia, and parkinsonism, lasting 10 years to her death. Histopathologic findings included an intense focus of multicentric PrP-plaques within the hippocampus, punctate plaques scattered throughout the cerebellum, and intense spongiform degeneration focally within the putamen, suggesting a variant of Gerstmann-Sträussler-Scheinker syndrome (GSS). However, PrP^Sc-typing revealed two PK-resistant PrP^Sc fragments (∼21 and 26 kDa), a pattern not previously detected in GSS.

Conclusions: This mutation is the third sequence variation at codon 105 of PRNP. The unusual phenotype and PrP^Sc-type distinguishes this genetic prion disease from typical Gerstmann-Sträussler-Scheinker syndrome and other codon 105 substitutions, suggesting that, in addition to the loss of proline at this position, the PrP^Sc conformation and phenotype is dependent on the specific amino acid substitution.