Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein

Wen Quan Zou, Gianfranco Puoti, Xiangzhu Xiao, Jue Yuan, Liuting Qing, Ignazio Cali, Miyuki Shimoji, Jan P M Langeveld, Rudy Castellani, Silvio Notari, Barbara Crain, Robert E. Schmidt, Michael Geschwind, Stephen J. DeArmond, Nigel J. Cairns, Dennis W Dickson, Lawrence Honig, Juan Maria Torres, James Mastrianni, Sabina CapellariGiorgio Giaccone, Ermias D. Belay, Lawrence B. Schonberger, Mark Cohen, George Perry, Qingzhong Kong, Piero Parchi, Fabrizio Tagliavini, Pierluigi Gambetti

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.

Original languageEnglish (US)
Pages (from-to)162-172
Number of pages11
JournalAnnals of Neurology
Volume68
Issue number2
DOIs
StatePublished - 2010

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Prion Diseases
Peptide Hydrolases
Valine
Methionine
Genotype
Creutzfeldt-Jakob Syndrome
Codon
Open Reading Frames
Genes
Digestion
Prion Proteins
Pathology
Phenotype
Mutation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Medicine(all)

Cite this

Zou, W. Q., Puoti, G., Xiao, X., Yuan, J., Qing, L., Cali, I., ... Gambetti, P. (2010). Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein. Annals of Neurology, 68(2), 162-172. https://doi.org/10.1002/ana.22094

Variably protease-sensitive prionopathy : A new sporadic disease of the prion protein. / Zou, Wen Quan; Puoti, Gianfranco; Xiao, Xiangzhu; Yuan, Jue; Qing, Liuting; Cali, Ignazio; Shimoji, Miyuki; Langeveld, Jan P M; Castellani, Rudy; Notari, Silvio; Crain, Barbara; Schmidt, Robert E.; Geschwind, Michael; DeArmond, Stephen J.; Cairns, Nigel J.; Dickson, Dennis W; Honig, Lawrence; Torres, Juan Maria; Mastrianni, James; Capellari, Sabina; Giaccone, Giorgio; Belay, Ermias D.; Schonberger, Lawrence B.; Cohen, Mark; Perry, George; Kong, Qingzhong; Parchi, Piero; Tagliavini, Fabrizio; Gambetti, Pierluigi.

In: Annals of Neurology, Vol. 68, No. 2, 2010, p. 162-172.

Research output: Contribution to journalArticle

Zou, WQ, Puoti, G, Xiao, X, Yuan, J, Qing, L, Cali, I, Shimoji, M, Langeveld, JPM, Castellani, R, Notari, S, Crain, B, Schmidt, RE, Geschwind, M, DeArmond, SJ, Cairns, NJ, Dickson, DW, Honig, L, Torres, JM, Mastrianni, J, Capellari, S, Giaccone, G, Belay, ED, Schonberger, LB, Cohen, M, Perry, G, Kong, Q, Parchi, P, Tagliavini, F & Gambetti, P 2010, 'Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein', Annals of Neurology, vol. 68, no. 2, pp. 162-172. https://doi.org/10.1002/ana.22094
Zou, Wen Quan ; Puoti, Gianfranco ; Xiao, Xiangzhu ; Yuan, Jue ; Qing, Liuting ; Cali, Ignazio ; Shimoji, Miyuki ; Langeveld, Jan P M ; Castellani, Rudy ; Notari, Silvio ; Crain, Barbara ; Schmidt, Robert E. ; Geschwind, Michael ; DeArmond, Stephen J. ; Cairns, Nigel J. ; Dickson, Dennis W ; Honig, Lawrence ; Torres, Juan Maria ; Mastrianni, James ; Capellari, Sabina ; Giaccone, Giorgio ; Belay, Ermias D. ; Schonberger, Lawrence B. ; Cohen, Mark ; Perry, George ; Kong, Qingzhong ; Parchi, Piero ; Tagliavini, Fabrizio ; Gambetti, Pierluigi. / Variably protease-sensitive prionopathy : A new sporadic disease of the prion protein. In: Annals of Neurology. 2010 ; Vol. 68, No. 2. pp. 162-172.
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AU - Zou, Wen Quan

AU - Puoti, Gianfranco

AU - Xiao, Xiangzhu

AU - Yuan, Jue

AU - Qing, Liuting

AU - Cali, Ignazio

AU - Shimoji, Miyuki

AU - Langeveld, Jan P M

AU - Castellani, Rudy

AU - Notari, Silvio

AU - Crain, Barbara

AU - Schmidt, Robert E.

AU - Geschwind, Michael

AU - DeArmond, Stephen J.

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AU - Torres, Juan Maria

AU - Mastrianni, James

AU - Capellari, Sabina

AU - Giaccone, Giorgio

AU - Belay, Ermias D.

AU - Schonberger, Lawrence B.

AU - Cohen, Mark

AU - Perry, George

AU - Kong, Qingzhong

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AU - Tagliavini, Fabrizio

AU - Gambetti, Pierluigi

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N2 - Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.

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