Novel Missense Variants of Prion Protein in Creutzfeldt-Jakob Disease or Gerstmann-Sträussler Syndrome

doi:10.1006/bbrc.1993.1275

Biochemical and Biophysical Research Communications

Volume 191, Issue 2, 15 March 1993, Pages 709-714

https://doi.org/10.1006/bbrc.1993.1275 Get rights and content

Abstract

We found 3 novel missense variants in the open reading frame of the prion protein (PrP) gene. The codon 105 point mutation (praline to leucine) was found on a codon 129 (Valine) PrP allele in 4 patients from 3 different Japanese families with Gerstmann-Sträussler syndrome. The codon 180 variant PrP (valine to isoleucine) was found in Creutzfeldt-Jakob disease (CJD) patients with a similar clinical course to that of codon 178 mutation. The codon 232 variant PrP (methionine to arginine) was documented in the CJD patients with typical clinical and pathological findings. These variant PrP molecules were not detected in 200 normal Japanese PrP alleles. PrP has a large repertoire of variant forms, and each primary structure of PrP corresponds to the distinct phenotype of prion diseases.

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Cited by (165)

Preventive or promotive effects of PRNP polymorphic heterozygosity on the onset of prion disease
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The polymorphic heterozygosity of PRNP at codon 129 or 219 prevents the onset of sporadic Creutzfeldt-Jakob disease (sCJD). We investigated the association between polymorphic genotypes at codon 129 or 219 and comprehensive prion disease onset using non-CJD as a reference. EK heterozygotes at codon 219, versus EE homozygotes, showed a preventive effect on the extensive prion diseases―sCJD, genetic CJD (gCJD) with V180I or M232R mutation, and Gerstmann-Straussler-Scheinker disease with P102L mutation. No preventive effect was observed for E200K-gCJD and dura-grafted CJD (dCJD) in 129 MV and 219 EK heterozygotes. It was suggested that unlike other prion diseases, E200K-gCJD may not benefit from the preventive effect of 219 EK heterozygosity because complementary electrostatic interactions between PrP molecules at K200 and E219 might make homodimer formation easier. Comparison of sCJD and dCJD indicates that 219 EK heterozygosity strongly inhibits de novo synthesis of PrP^Sc (initial PrP^Sc formation), but does not inhibit accelerated propagation of existing PrP^Sc.
Specific electroencephalogram features in the very early phases of sporadic Creutzfeldt–Jakob disease
2022, Journal of the Neurological Sciences
Studies on the very early electroencephalography (EEG) features prior to the emergence of generalized periodic discharges (GPDs, generally known as periodic sharp-wave complexes) in Creutzfeldt–Jakob disease (CJD) are rare. Fourteen patients with sporadic CJD (sCJD) (eight with MM1/classic and six with MM2c) were included in this study. The predominant findings of the first EEG were categorized as 1) lateralized periodic discharges (LPDs), 2) central sagittal sporadic epileptiform discharges (CSSEDs) showing midline predominant generalized spike-and-wave complexes and/or sharp waves in the central sagittal regions, or 3) focal epileptiform discharges. Clinical records, magnetic resonance imaging (MRI), and changes in EEG were compared between three groups (LPD in MM1/classic, CSSED in MM1/classic, and focal epileptiform discharge in MM2c). Three (37.5%) and five (62.5%) patients with MM1/classic sCJD were classified into the LPD and CSSED groups, respectively. Patients in the LPD group were accompanied by cortical hyperintensities at the corresponding areas on MRI, while those in the CSSED group showed hyperintensities on MRI at unassociated cortical areas. Follow-up EEG of three (100%) patients in the LPD group and four (80%) in the CSSED group showed transitions to GPDs. All patients with MM1/classic sCJD showed myoclonus on initial EEG, and the symptomatic side was opposite to the hemisphere showing LPDs or higher-amplitude central sagittal epileptiform activity. The periodicity after these EEGs likely contributes to the diagnostic confidence of physicians when patients are in the very early stages of MM1/classic sCJD.
α2,3 linkage of sialic acid to a GPI anchor and an unpredicted GPI attachment site in human prion protein
2020, Journal of Biological Chemistry
Prion diseases are transmissible, lethal neurodegenerative disorders caused by accumulation of the aggregated scrapie form of the prion protein (PrP^Sc) after conversion of the cellular prion protein (PrP^C). The glycosylphosphatidylinositol (GPI) anchor of PrP^C is involved in prion disease pathogenesis, and especially sialic acid in a GPI side chain reportedly affects PrP^C conversion. Thus, it is important to define the location and structure of the GPI anchor in human PrP^C. Moreover, the sialic acid linkage type in the GPI side chain has not been determined for any GPI-anchored protein. Here we report GPI glycan structures of human PrP^C isolated from human brains and from brains of a knock-in mouse model in which the mouse prion protein (Prnp) gene was replaced with the human PRNP gene. LC–electrospray ionization–MS analysis of human PrP^C from both biological sources indicated that Gly²²⁹ is the ω site in PrP^C to which GPI is attached. Gly²²⁹ in human PrP^C does not correspond to Ser²³¹, the previously reported ω site of Syrian hamster PrP^C. We found that ∼41% and 28% of GPI anchors in human PrP^Cs from human and knock-in mouse brains, respectively, have N-acetylneuraminic acid in the side chain. Using a sialic acid linkage-specific alkylamidation method to discriminate α2,3 linkage from α2,6 linkage, we found that N-acetylneuraminic acid in PrP^C's GPI side chain is linked to galactose through an α2,3 linkage. In summary, we report the GPI glycan structure of human PrP^C, including the ω-site amino acid for GPI attachment and the sialic acid linkage type.
A Novel Combination of Prion Strain Co-Occurrence in Patients with Sporadic Creutzfeldt-Jakob Disease
2019, American Journal of Pathology
Six subgroups of sporadic Creutzfeldt-Jakob disease have been identified by distinctive clinicopathologic features, genotype at polymorphic codon 129 [methionine (M)/valine (V)] of the PRNP gene, and type of abnormal prion proteins (type 1 or 2). In addition to the pure subgroups, mixed neuropathologic features and the coexistence of two types of abnormal prion proteins in the same patient also have been reported. Here, we found that a portion of the patients previously diagnosed as MM1 had neuropathologic characteristics of the MM2 thalamic form (ie, neuronal loss of the inferior olivary nucleus of the medulla). Furthermore, coexistence of biochemical features of the MM2 thalamic form also was confirmed in the identified cases. In addition, in transmission experiments using prion protein–humanized mice, the brain material from the identified case showed weak infectivity and generated characteristic abnormal prion proteins in the inoculated mice resembling those after inoculation with brain material of MM2 thalamic form. Taken together, these results show that the co-occurrence of MM1 and MM2 thalamic form is a novel entity of sporadic Creutzfeldt-Jakob disease prion strain co-occurrence. The present study raises the possibility that the co-occurrence of the MM2 thalamic form might have been overlooked so far because of the scarcity of abnormal prion protein accumulation and restricted neuropathology.
Diffusion-weighted imaging negative M232R familial Creutzfeldt-Jakob disease
2019, Journal of Clinical Neuroscience
Citation Excerpt :
At the 17 months after onset, myoclonus was detected in the bilateral upper extremities. Since CJD with the M232R mutation was first described in two unrelated Japanese patients in 1993 [3], this mutation has only been found in Asian-not in Caucasian-CJD patients [4–12]. Shiga et al. examined the clinical and laboratory features of 20 fCJD (M232R) patients, and reported that those with fCJD (M232R) usually have no family history and have two clinical phenotypes: a rapidly progressive type; and a slowly progressive type [6].
The familial Creutzfeldt-Jakob disease (fCJD) usually has similar clinical and neuroimaging features as sporadic CJD (sCJD). A 57-year-old man presented with a four-month history of rapidly progressive dementia (RPD). Laboratory tests for RPD were all normal. Brain MRI demonstrated diffuse cortical atrophy and no abnormal cortical or striatal hyperintensities on fluid-attenuated inversion recovery (FLAIR)/diffusion weighted imaging (DWI). Electroencephalography revealed intermittent slow waves in the bilateral hemispheres. Cerebrospinal fluid (CSF) examination showed elevated cell counts and protein concentrations. After 10 days of empirical treatment with antiviral agents, the patient was eventually diagnosed with fCJD with M232R mutation based on the results of positivity for 14-3-3 protein, CSF PrP^sc in real-time quaking-induced conversion assay and genetic test for PRNP gene. The striatal or cortical FLAIR/DWI hyperintensities are reliable radiographic markers in the diagnosis of both sCJD and fCJD. However, this case suggests that clinical work-up for CJD including genetic test is essential to do a differential diagnosis of RPD, regardless of FLAIR/DWI findings.
Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to-isoleucine substitution at codon 180 on the prion protein gene
2018, Biochemical and Biophysical Research Communications
Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrP^res at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrP^res in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrP^res were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease.

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Regular ArticleNovel Missense Variants of Prion Protein in Creutzfeldt-Jakob Disease or Gerstmann-Sträussler Syndrome

Abstract

Regular Article
Novel Missense Variants of Prion Protein in Creutzfeldt-Jakob Disease or Gerstmann-Sträussler Syndrome