V180I mutation of the prion protein gene associated with atypical PrPSc glycosylation

doi:10.1016/j.neulet.2006.08.008

Neuroscience Letters

Volume 408, Issue 3, 20 November 2006, Pages 165-169

https://doi.org/10.1016/j.neulet.2006.08.008 Get rights and content

Abstract

A valine to isoleucine mutation at residue 180 was identified in a French patient with Creutzfeldt-Jakob disease (CJD). The mutation is located in the close vicinity of one of the two N-glycosylation sites of the cellular prion protein (PrP^C). Western blot analysis revealed accumulation in the brain of the pathogenic proteinase K-resistant PrP (PrP^Sc) isoform with the notable absence of the diglycosylated band. The mutant protein expressed in CHO cells was correctly glycosylated, suggesting that the atypical glycosylation pattern of PrP^Sc was not due to the mutation at position 180. These results suggest that the diglycosylated form of the mutant PrP^180I prevents its conversion into the pathogenic mutant form PrP^Sc180I, supporting a central role of N-linked glycan chains in the PrP conversion process.

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Acknowledgements

We are grateful to Dr. J. Grassi for SAF70, Pr. S. Lehmann for pcDNA3 initial constructs and Dr. M. Ermonval for helpful discussions.

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Genetic Creutzfeldt–Jakob disease
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Citation Excerpt :
A case report mentioned intraneuronal deposits (Nixon et al., 2000), reminiscent of those seen in a subset of E200K genetic CJD cases (Kovacs et al., 2012). Western blot revealed type 1 or 2 PrPres together with the peculiar feature of the lack of the diglycoform band (Chasseigneaux et al., 2006; Iwasaki et al., 2011). The threonine (T) to alanine (A) change at codon 183 (T183A) was first found in a Brazilian family of Spanish and Italian origin in two affected members and in 12 healthy family members (Nitrini et al., 1997).
Genetic Creutzfeldt–Jakob disease (CJD) is associated with mutations in the human PrP gene (PRNP) on chromosome 20p12-pter. Pathogenic mutations have been identified in 10–15% of all CJD patients, who often have a family history of autosomal-dominant pattern of inheritance and variable penetrance. However, the use of genetic tests implemented by surveillance networks all over the world increasingly identifies unexpectedly PRNP mutations in persons apparently presenting with a sporadic form of CJD. A high phenotypic variability was reported in genetic prion diseases, which partly overlap with the features of sporadic CJD. Here we review recent advances on the epidemiologic, clinical, and neuropathologic features of cases that phenotypically resemble CJD linked to point and insert mutations of the PRNP gene. Multidisciplinary studies are still required to understand the phenotypic spectrum, penetrance, and significance of PRNP mutations.
Familial Creutzfeldt-Jakob disease with a mutation at codon 180 presenting with an atypical phenotype
2013, Journal of Clinical Neuroscience
Citation Excerpt :
This suggests that the epitope of the fragment is around PrP 109-113 (mAb 3F4). An atypical pattern of PrPres without the highest molecular weight fragment has been reported in a patient with fCJD (V180I), although its reason and significance is uncertain.6 In summary, our patient with fCJD (V180I) showed atypical clinical manifestations, neuroimaging results, and Western analysis of PrPres, which differed from those reported for fCJD patients with the same mutation.
The clinical features of familial Creutzfeldt–Jakob disease (fCJD) with a mutation at codon 180 (V180I) are less typical than those of patients with sporadic CJD. We describe a patient with pathologically confirmed CJD carrying the V180I mutation who had atypical cerebrospinal fluid and electroencephalography findings. Similar to other prion protein mutations, this report suggests that the V180I mutation is not the exclusive determinant of the phenotype.
Serial diffusion-weighted MRI and SPECT findings in a Creutzfeldt-Jakob disease patient with V180I mutation
2011, Journal of the Neurological Sciences
Citation Excerpt :
Postmortem pathologic examination was not permitted. CJD, with a causative point mutation of V180I in the prion protein gene, is a rare type of familial CJD (fCJD), with only 2 cases reported from Europe [7,8]; however, this mutation is recognized as the most common cause of fCJD in Japan. Jin et al. reported the clinical and laboratory characteristics of CJD patients with the V180I (CJD180) by comparing them with those of sCJD.
We report serial changes of diffusion-weighted imaging (DWI) and single photon emission computed tomography (SPECT) in a patient with Creutzfeldt–Jakob disease with V180I mutation (CJD180). DWI abnormalities in our patient were more predominantly observed in the left cerebral cortex than left basal ganglia. Hemilateral abnormalities progressed over 5 months to involve the contralateral side with increasing DWI signals. At 6 months, SPECT showed hypoperfusion in the left parietal and frontal lobes and the hypoperfusion region spread to the bilateral basal ganglia, right parietal and frontal lobes. SPECT imaging revealed marked cerebral blood flow reduction, predominantly in the cerebral cortex corresponding to brain areas with high-intensity DWI signals. During the follow-up period of CJD180, DWI was more sensitive than conventional FLAIR and T2-weighted images (T2WI) to detect and monitor the progression of abnormal hyperintense lesions. We suggest that serial DWI and SPECT findings are useful for not only early diagnosis of CJD but also for monitoring disease progression.
Pathogenic Mutations in the Hydrophobic Core of the Human Prion Protein Can Promote Structural Instability and Misfolding
2010, Journal of Molecular Biology
Citation Excerpt :
Our simulations indicate that misfolding might happen in a fashion similar to that of WT PrP, but conformational changes unlike those observed in WT PrP were found as well. In contrast to sporadic or V210I CJD, deposits of V180I PrPSc are never diglycosylated52 and V180I CJD cannot be transmitted to mice expressing WT PrP.53 Clinical and pathological symptoms as well as the average duration of disease (> 16 months) also differ from sporadic CJD.54,55
Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. These diseases can be hereditary in humans and four of the many disease-associated missense mutants of PrP are in the hydrophobic core: V180I, F198S, V203I and V210I. The T183A mutation is related to the hydrophobic core mutants as it is close to the hydrophobic core and known to cause instability. We used extensive molecular dynamics simulations of these five PrP mutants to compare their dynamics and conformations to those of the wild type PrP. The simulations highlight the changes that occur upon introduction of mutations and help to rationalize experimental findings. Changes can occur around the mutation site, but they can also be propagated over long distances. In particular, the F198S and T183A mutations lead to increased flexibility in parts of the structure that are normally stable, and the short β-sheet moves away from the rest of the protein. Mutations V180I, V210I and, to a lesser extent, V203I cause changes similar to those observed upon lowering the pH, which has been linked to misfolding. Early misfolding is observed in one V180I simulation. Overall, mutations in the hydrophobic core have a significant effect on the dynamics and stability of PrP, including the propensity to misfold, which helps to explain their role in the development of familial prion diseases.
V180I genetic Creutzfeldt-Jakob disease: Severe degeneration of the inferior olivary nucleus in an autopsied patient with identification of the M2T prion strain
2023, Neuropathology
Glycoform-Selective Prions in Sporadic and Genetic Variably Protease-Sensitive Prionopathies
2023, Prions and Diseases: Second Edition

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V180I mutation of the prion protein gene associated with atypical PrPSc glycosylation

Abstract

Section snippets

Acknowledgements

Am. J. Pathol.

J. Neurol. Sci.

Biochem. Biophys. Res. Commun.

Am. J. Pathol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

Biases and complex patterns in the residues flanking protein N-glycosylation sites

Glycobiology

The Thr183Ala mutation, not the loss of the first glycosylation site, alters the physical properties of the prion protein

J. Alzheimers. Dis.

Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD

Nature

Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease

N. Engl. J. Med.

Loss of glycosylation associated with the T183A mutation in human prion disease

Acta Neuropathol. (Berl).

V180I mutation of the prion protein gene associated with atypical PrP^Sc glycosylation