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

W.Q. Zou, G. Puoti, X. Xiao, J. Yuan, L. Qing, I. Cali, M. Shimoji, J.P.M. Langeveld, R. Castellani, S. Notari, B. Crain, R. Schmidt, M. Geschwind, S.J. DeArmond, N. Cairns, D. Dickson, I. Honig, J.M. Torres, J. Mastrianni, S. Capellari & 9 others G. Giaccone, E.D. Belay, L.B. Schonberger, M. Cohen, G. Perry, Q. Kong, P. Parchi, F. Tagliavini, P. Gambetti

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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-Straussler-Scheinker disease. ANN NEUROL 2010;68:162-172
Original languageEnglish
Pages (from-to)162-172
JournalAnnals of Neurology
Volume68
Issue number2
DOIs
Publication statusPublished - 2010

Fingerprint

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

Keywords

  • creutzfeldt-jakob-disease
  • gerstmann-straussler-scheinker
  • codon 129
  • prp
  • cjd
  • classification
  • transmission
  • phenotype
  • subtypes
  • brain

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
Zou, W.Q. ; Puoti, G. ; Xiao, X. ; Yuan, J. ; Qing, L. ; Cali, I. ; Shimoji, M. ; Langeveld, J.P.M. ; Castellani, R. ; Notari, S. ; Crain, B. ; Schmidt, R. ; Geschwind, M. ; DeArmond, S.J. ; Cairns, N. ; Dickson, D. ; Honig, I. ; Torres, J.M. ; Mastrianni, J. ; Capellari, S. ; Giaccone, G. ; Belay, E.D. ; Schonberger, L.B. ; Cohen, M. ; Perry, G. ; Kong, Q. ; Parchi, P. ; Tagliavini, F. ; Gambetti, P. / 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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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-Straussler-Scheinker disease. ANN NEUROL 2010;68:162-172",
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author = "W.Q. Zou and G. Puoti and X. Xiao and J. Yuan and L. Qing and I. Cali and M. Shimoji and J.P.M. Langeveld and R. Castellani and S. Notari and B. Crain and R. Schmidt and M. Geschwind and S.J. DeArmond and N. Cairns and D. Dickson and I. Honig and J.M. Torres and J. Mastrianni and S. Capellari and G. Giaccone and E.D. Belay and L.B. Schonberger and M. Cohen and G. Perry and Q. Kong and P. Parchi and F. Tagliavini and P. Gambetti",
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Zou, WQ, Puoti, G, Xiao, X, Yuan, J, Qing, L, Cali, I, Shimoji, M, Langeveld, JPM, Castellani, R, Notari, S, Crain, B, Schmidt, R, Geschwind, M, DeArmond, SJ, Cairns, N, Dickson, D, Honig, I, 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

Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein. / Zou, W.Q.; Puoti, G.; Xiao, X.; Yuan, J.; Qing, L.; Cali, I.; Shimoji, M.; Langeveld, J.P.M.; Castellani, R.; Notari, S.; Crain, B.; Schmidt, R.; Geschwind, M.; DeArmond, S.J.; Cairns, N.; Dickson, D.; Honig, I.; Torres, J.M.; Mastrianni, J.; Capellari, S.; Giaccone, G.; Belay, E.D.; Schonberger, L.B.; Cohen, M.; Perry, G.; Kong, Q.; Parchi, P.; Tagliavini, F.; Gambetti, P.

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

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein

AU - Zou, W.Q.

AU - Puoti, G.

AU - Xiao, X.

AU - Yuan, J.

AU - Qing, L.

AU - Cali, I.

AU - Shimoji, M.

AU - Langeveld, J.P.M.

AU - Castellani, R.

AU - Notari, S.

AU - Crain, B.

AU - Schmidt, R.

AU - Geschwind, M.

AU - DeArmond, S.J.

AU - Cairns, N.

AU - Dickson, D.

AU - Honig, I.

AU - Torres, J.M.

AU - Mastrianni, J.

AU - Capellari, S.

AU - Giaccone, G.

AU - Belay, E.D.

AU - Schonberger, L.B.

AU - Cohen, M.

AU - Perry, G.

AU - Kong, Q.

AU - Parchi, P.

AU - Tagliavini, F.

AU - Gambetti, P.

PY - 2010

Y1 - 2010

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-Straussler-Scheinker disease. ANN NEUROL 2010;68:162-172

AB - 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-Straussler-Scheinker disease. ANN NEUROL 2010;68:162-172

KW - creutzfeldt-jakob-disease

KW - gerstmann-straussler-scheinker

KW - codon 129

KW - prp

KW - cjd

KW - classification

KW - transmission

KW - phenotype

KW - subtypes

KW - brain

U2 - 10.1002/ana.22094

DO - 10.1002/ana.22094

M3 - Article

VL - 68

SP - 162

EP - 172

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 2

ER -