Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease

Piero Parchi, Rudolph Castellani, Sabina Capellari, Bernardino Ghetti, Katherine Young, Shu G. Chen, Martin Farlow, Dennis W Dickson, Anders A F Sima, John Q. Trojanowski, Robert B. Petersen, Pierluigi Gambetti

Research output: Contribution to journalArticle

653 Citations (Scopus)

Abstract

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the priori protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt- Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to 'type 1' protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the 'type 2' protease- resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

Original languageEnglish (US)
Pages (from-to)767-778
Number of pages12
JournalAnnals of Neurology
Volume39
Issue number6
DOIs
StatePublished - Jun 1996
Externally publishedYes

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Peptide Hydrolases
Codon
Methionine
Creutzfeldt-Jakob Syndrome
Valine
Kuru
Genotype
Prions
Sporadic Creutzfeldt-Jakob Disease
Prion Proteins
Glycosylation
Genes
Dementia
Western Blotting
Immunohistochemistry
Phenotype
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Parchi, P., Castellani, R., Capellari, S., Ghetti, B., Young, K., Chen, S. G., ... Gambetti, P. (1996). Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Annals of Neurology, 39(6), 767-778. https://doi.org/10.1002/ana.410390613

Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. / Parchi, Piero; Castellani, Rudolph; Capellari, Sabina; Ghetti, Bernardino; Young, Katherine; Chen, Shu G.; Farlow, Martin; Dickson, Dennis W; Sima, Anders A F; Trojanowski, John Q.; Petersen, Robert B.; Gambetti, Pierluigi.

In: Annals of Neurology, Vol. 39, No. 6, 06.1996, p. 767-778.

Research output: Contribution to journalArticle

Parchi, P, Castellani, R, Capellari, S, Ghetti, B, Young, K, Chen, SG, Farlow, M, Dickson, DW, Sima, AAF, Trojanowski, JQ, Petersen, RB & Gambetti, P 1996, 'Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease', Annals of Neurology, vol. 39, no. 6, pp. 767-778. https://doi.org/10.1002/ana.410390613
Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Annals of Neurology. 1996 Jun;39(6):767-778. https://doi.org/10.1002/ana.410390613
Parchi, Piero ; Castellani, Rudolph ; Capellari, Sabina ; Ghetti, Bernardino ; Young, Katherine ; Chen, Shu G. ; Farlow, Martin ; Dickson, Dennis W ; Sima, Anders A F ; Trojanowski, John Q. ; Petersen, Robert B. ; Gambetti, Pierluigi. / Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. In: Annals of Neurology. 1996 ; Vol. 39, No. 6. pp. 767-778.
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