NovelPRNP sequence variant associated with familial encephalopathy

Abstract

Human transmissible spongiform encephalopathies (TSEs) are a group of chronic progressive neurodegenerative disorders that may be hereditary, infectious, or sporadic. Hereditary TSEs are associated with mutations in the PRNP gene on chromosome 20p12-pter. We report on a family in which seven patients developed limb and truncal ataxia, dysarthria, myoclonic jerks, and cognitive decline. The age of onset in the 30s, 40s, or 50s, prolonged disease duration, cerebellar atrophy on imaging, and the presence of synchronic periodic discharges on electroencephalogram suggested a familial encephalopathy resembling Gerstmann-Sträussler-Scheinker disease. A novel H187R mutation has been identified in affected, but not in unaffected, family members or unrelated controls suggesting a pathogenic role for this mutation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:653-656, 1999. Published 1999 Wiley-Liss, Inc.

Instability of familial spongiform encephalopathy-related prion mutants

“…His 187 is reported to be involved in a pathogenic mutation associated with GSS syndrome (H187R) [9,10]. A recent study indicated that the breaking of the salt bridge (E195-R156) induced by the protonation of H187 at acidic pH was the key event underlying the extension of the S2 region [11].…”

“…Thus, it was proposed that the neutralization of D178 at low pH removes interactions that inhibit a structural change at neutral pH. In addition, His 187 (H187) has also been reported to be involved into a pathogenic mutation associated with GSS syndrome (H187R), which implies a positively charged residue in position 187, analogous to H187 protonation [9,10]. A recent study suggested that the breaking of the salt bridge between Glu 195 and Arg 156 induced by the protonation of H187 at acidic pH was the key event underlying the extension of the S2 4 region [11].…”

Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides

“…Recent spectroscopic experiments [49,80] exclude the involvement of H140 in Cu 2+ binding, but the aggregation of model peptides hampered characterization of the metal interaction with H177 and caused uncertainty about Cu 2+ binding to His 187 at physiological pH. Incidentally, it has been found [81,82] that the only known histidine variant associated with familial encephalopathy could be associated with the H187R mutation in the PrP gene. Brown and co-authors [49] characterized Cu 2+ complexes with two analogues of the peptide fragment 180-193 (VNITKQHTVTTTT), which almost entirely encompasses the PrP C 's 2-helix, one with blocked and the other with free C-and N-termini.…”

A novel copper(II) coordination at His186 in full-length murine prion protein

“…in the human is reported to be involved in a pathogenic mutation (H187R) associated with GSS syndrome, which implies a positively charged residue at position 187 [32]. This H187R mutation may induce the break of the salt bridge in a manner similar to that induced by protonation of His187 under acidic pH.…”

“…Langella et al proposed that His187 and Glu196 were the most probable candidates for binding residues of Cu(II) ion according to their computer simulation and that H187R mutation was related to altered Cu(II) binding [32]. These reports and our results suggested that this disruption of the interaction between Cu(II) ion and PrP C by a point mutation of His187 in the human influenced the C-terminal core structure related to induction of prion diseases such as GSS syndrome.…”