Molecular genetics of prion diseases in France

Laplanche, Jean‐Louis; Delasnerie-Lauprêtre, N; Brandel, J.-P.; Chatelain, J; Beaudry, P.; Alpérovitch, Annick; Launay, J. M.

doi:10.1212/wnl.44.12.2347

Cited by 108 publications

(51 citation statements)

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“…Systematic examination of the coding sequence of the prion protein gene (PRNP) revealed that 10 patients carried a mutation (9 E200K and 1 P102L), but none had a documented familial history of CJD. Among the 59 definite and probable patients without PRNP mutation, 46 (78%) encoded methionine on both alleles at polymorphic codon 129, 6 (10%) were valine homozygous, and 7 (12%) heterozygous, in accordance with previous studies [20,21].…”

Section: Methodssupporting

confidence: 89%

14-3-3 Protein, Neuron-Specific Enolase, and S-100 Protein in Cerebrospinal Fluid of Patients with Creutzfeldt-Jakob Disease

Beaudry

Cohen

et al. 1998

Dement Geriatr Cogn Disord

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142

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We explored simultaneously 14-3-3 protein, neuron-specific enolase (NSE), and one astroglial protein, S-100, recently proposed as Creutzfeld-Jakob disease (CJD) markers, in the cerebrospinal fluid (CSF) of 129 patients with suspected CJD. Cutoff values for NSE and S-100 were established at 25 and 2.5 ng/ml, respectively. The highest sensitivity was observed for S-100 (94.2%) followed by 14-3-3 (89.8%) and NSE (79.7%), while the highest specificity in CJD diagnosis was obtained with 14-3-3 protein (100%) as compared with NSE (91.5%) and S-100 (85.4%). No influence of sex, genotype at codon 129 of the prion protein gene, time between sampling, and death or disease duration has been found. Based on 90 cases initially referred as ‘probable’ or ‘possible’ CJD, with 14-3-3, NSE, or S-100 we could correctly discriminate between ‘CJD’ or ‘non-CJD’ categories in 94.4, 86.5, and 90% of the cases, respectively. When limited to ‘possible CJD’ cases, diagnosis based on one of the three CSF proteins was accurate in 98, 90.7 and 87.3%, respectively. In view of the fact that the CSF 14-3-3 protein test alone has the highest specificity and good sensitivity, it appears that there is no additional advantage at the moment to include NSE and/or S-100 protein in the exploration of clinically suspected CJD cases.

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Section: Methodssupporting

confidence: 89%

14-3-3 Protein, Neuron-Specific Enolase, and S-100 Protein in Cerebrospinal Fluid of Patients with Creutzfeldt-Jakob Disease

Beaudry

Cohen

et al. 1998

Dement Geriatr Cogn Disord

Self Cite

142

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“…Although the physiological function of PrP, if any, remains obscure, it may be that the maintenance of this polymorphism results from the selective pressure of prion diseases. There is evidence that the polymorphism affects susceptibility to sporadic (3,4) and acquired (5, 6) prion diseases and of features such as their age of onset and pathological presentation (7)(8)(9). Most strikingly, M129V heterozygotes appear to be relatively protected from sporadic, inherited, and infectious prion diseases in these studies.…”

mentioning

confidence: 70%

Molecular Heterosis of Prion Protein β-Oligomers

Tahiri-Alaoui

Sim

Caughey

et al. 2006

Journal of Biological Chemistry

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The gene encoding prion protein is polymorphic in human populations, with over 40% of native Europeans, for example, being heterozygous for the Met-129 and Val-129 alleles. The polymorphism affects both the incidence and the clinical presentation of a range of prion diseases, with heterozygotes generally showing the highest levels of resistance. It has been suggested that an earlier epidemic of prion diseases exerted balancing selection on the two alleles, and we have previously demonstrated that the two encoded proteins have potentially compensating tendencies to form amyloid and soluble ␤-oligomers, respectively, in vitro. More strikingly, here we demonstrate that mixed oligomers, composed of both allelic forms, show an extreme sluggishness in converting to amyloid in comparison with oligomers homogenous for either allele. It may be that this example of molecular heterosis in vitro provides the basis for maintenance of the polymorphism in the population and that ␤-oligomers represent a form of PrP sequestered from pathogenic amyloid formation in vivo.

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“…[31][32][33][34] Nearly 90% of patients were homozygous at codon 129 with most having the genotype MM.…”

Section: Molecular Analysismentioning

confidence: 99%

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects

Parchi¹,

Giese²,

Capellari³

et al. 1999

Ann Neurol.

1,244

693

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Phenotypic heterogeneity in sporadic Creutzfeldt‐Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease‐resistant prion protein (PrPSc) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrPSc properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrPSc deposition. Seventy percent of subjects showed the classic CJD phenotype, PrPSc type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru‐plaque variants, associated to PrPSc type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrPSc type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrPSc type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants. Ann Neurol 1999;46:224–233

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Molecular genetics of prion diseases in France

Cited by 108 publications

References 0 publications

14-3-3 Protein, Neuron-Specific Enolase, and S-100 Protein in Cerebrospinal Fluid of Patients with Creutzfeldt-Jakob Disease

14-3-3 Protein, Neuron-Specific Enolase, and S-100 Protein in Cerebrospinal Fluid of Patients with Creutzfeldt-Jakob Disease

Molecular Heterosis of Prion Protein β-Oligomers

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects

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