Phenotypic Heterogeneity of Variably Protease-Sensitive Prionopathy: A Report of Three Cases Carrying Different Genotypes at PRNP Codon 129

• Published in: Viruses 2022-02, Vol.14 (2), p.367
• Main Authors: Baiardi, Simone, Mammana, Angela, Rossi, Marcello, Ladogana, Anna, Carlà, Benedetta, Gambetti, Pierluigi, Capellari, Sabina, Parchi, Piero
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer's disease; amyloid; Apathy; Brain; Brain - metabolism; Brain - pathology; Cerebellum; Cerebrospinal fluid; Cloning; Codon; Diagnostic tests; Endopeptidase K; Endopeptidase K - metabolism; Female; Genotype; Genotype & phenotype; Genotypes; Humans; Immunoblotting; Immunohistochemistry; Magnetic resonance imaging; Male; Memory; Methionine; Mutation; Neuropathology; Patients; Phenotype; Physicochemical properties; Plaques; prion disease; Prion Diseases - diagnosis; Prion Diseases - metabolism; Prion Diseases - pathology; Prion protein; PRNP; protein misfolding; Protein seeding; Proteinase; Proteins; PrPSc Proteins - genetics; PrPSc Proteins - metabolism; scrapie; Valine; VPSPr
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v14020367

Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene ( ). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrP ), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrP profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV).