Report about Four Novel Mutations in the Prion Protein Gene

Abstract

Background/Aims: Since detection of the prion protein gene (PRNP) more than 30 mutations have been discovered. Some have only been found in single case reports without known intrafamilial accumulation or neuropathological proof so that the causal connection between mutation and disease could not be proved. Those patients often present atypical clinical phenotypes, and it is not unusual that they are classified as diseases other than Creutzfeldt-Jakob disease (CJD). Methods: Cases of suspected CJD have been reported to the national reference center for prion diseases. Clinical and diagnostic data were collected, and a classification of definite, possible or probable prion disease was made. Molecular analysis of PRNP was performed by capillary sequencing. Results: We have described 4 cases with atypical clinical and diagnostic findings and unknown mutations in PRNP so far. Conclusion: Three patients fulfilled the criteria of probable CJD, and 1 patient fulfilled the criteria of possible CJD but the clinical picture in none of the patients was typical CJD; hence, it remained questionable whether the mutations were causal of the disease.

Probing Early Misfolding Events in Prion Protein Mutants by NMR Spectroscopy

“…Therefore the pathological role of such rare mutations remains to be assessed. Recently new unclassified mutations have been discovered including Q52P in the OP, D167N in the β 2 -α 2 loop, N173K in α 2 -helix, V203G, V209M and Q212H in α 3 -helix [100,101]. Other confounding aspects are multiple mutations affecting the same codon and segregating with completely different clinico-pathological features, for instance P105L (linked to GSS) and P105T/V (unclassified disease phenotype), D202N (GSS) and D202G (unclassified), E211Q (CJD) and E211N (GSS), Q212P (GSS) and Q212H (unclassified).…”

Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein

“…In each case studied here, the system was enclosed in a periodic cubic box of size (300 Å) 3 . We used a replica exchange (also known as parallel tempering) procedure 59 to enhance the sampling in our simulations.…”

“…Prion diseases are associated with 58 missense or insertional/deletional mutations identified so far in the gene coding for HuPrP C ( PRNP ). Missense mutations include 44 nonsynonymous codon substitutions, or point mutations (PMs), and five nonsense (or “stop”) mutations. − These mutations lead to neurodegeneration and give rise to abnormal forms of HuPrP in the brain . The PMs are located all over the protein, from the disordered N-terminal domain (N-term_HuPrP C hereafter, residues 23–124) to the folded C-terminal globular domain (GD, residues 125–230; Figure A).…”

“…Few PMs are located in N-term_HuPrP C (Figure A). Q52P has been recently found in this domain, and it is likely associated with familial Creutzfeldt–Jakob disease (fCJD); G114V has been reported with both fCJD and Gerstmann–Sträussler–Scheinker syndrome (GSS), whereas P102L, P105L/S/T, and A117V are associated with GSS . The corresponding mutation of P102L in mouse (Mo) PrP C alters the incubation time in transgenic (Tg) mice upon infection by PrP Sc from Hu, hamster, sheep, or murine sources in a strain-dependent manner. , These N-terminal PMs cause the disease without affecting the kinetics of the HuPrP C to HuPrP Sc conversion in vitro .…”