A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease

Rodriguez, Matías; Peoc’h, Katell; Haı̈k, Stéphane; Bouchet, C; Vernengo, Luis; Mañana, G.; Salamano, Ronald; Carrasco, L.; Lenne, M.; Beaudry, P.; Launay, Jean‐Marie; Laplanche, Jean‐Louis

doi:10.1212/01.wnl.0000158618.39527.93

Cited by 47 publications

(40 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with the observations of the pathological abnormalities in the G114V gCJD patient (8,13), the transcriptional level of the GFAP gene associated with gliosis is increased and a series of genes associated with neurons are decreased. Although the brain tissues are severely damaged pathologically, the expression levels of prion protein gene PRNP do not differ distinctly compared with those of normal control, which is in accordance not only with the data of PRNP transcription in this patient with qRT-PCR, but also with the previous microarray findings in the sCJD patients (6), mice infected with scrapie or CJD agents (14) and cattle infected with the BSE agent (15).…”

Section: Discussionsupporting

confidence: 83%

Global transcriptional profiling of the postmortem brain of a patient with G114V genetic Creutzfeldt-Jakob disease

Tian

Chen

et al. 2013

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Abstract. Familial or genetic Creutzfeldt-Jakob disease (fCJD or gCJD) is an inherent human prion disease caused by mutation of the prion protein gene (PRNP). In the present study, global expression patterns of the parietal cortex from a patient with G114V gCJD were analyzed using the Affymetrix Human Genome U133+ 2.0 chip with a commercial normal human parietal cortex RNA pool as a normal control. In total, 8,774 genes showed differential expression; among them 2,769 genes were upregulated and 6,005 genes were downregulated. The reliability of the results was confirmed using real-time RT-PCR assays. The most differentially expressed genes (DEGs) were involved in transcription regulation, ion transport, transcription, cell adhesion, and signal transduction. The genes associated with gliosis were upregulated and the genes marked for neurons were downregulated, while the transcription of the PRNP gene remained unaltered. A total of 169 different pathways exhibited significant changes in the brain of G114V gCJD. The most significantly regulated pathways included Alzheimer's and Parkinson's disease, oxidative phosphorylation, regulation of actin cytoskeleton, MAPK signaling and proteasome, which have previously been linked to prion diseases. In addition, we found some pathways that have rarely been explored in regards to prion diseases that were also significantly altered in G114V gCJD, such as axon guidance, gap junction and purine metabolism. The majority of the genes in the 10 most altered pathways were downregulated. The data of the present study provide useful insights into the pathogenesis of G114V gCJD and potential biomarkers for diagnostic and therapeutic purposes. IntroductionPrion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative disorders in humans and animals, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathies (BSEs) in cattle, and scrapie in sheep and goats. The conversion of prion protein (PrP), coded by the PRNP gene, from its cellular isoform PrP C to its pathogenic isoform PrP Sc through a post-translational process is considered the etiology of these diseases. As a result of the conversion, the portion of β-sheets within PrP is increased (from 3 to 45%) whereas that of α-helices decreases (from 42 to 30%), therefore causing PrP to become detergent insoluble and resistant to denaturant (isoform PrP Sc ) (1). The conversion also causes a series of histopathological changes, including the depositions of PrP Sc , spongiform degenerations, neuronal loss and astrogliosis.According to the pathomechanisms, CJD can be classified into sporadic CJD (sCJD), familial or genetic CJD (fCJD or gCJD) and iatrogenic CJD (iCJD). fCJD accounts for approximately 10-15% of all CJD cases, characterized by the genetic changes of PrP (2). To date, 56 different mutations, including residue substitutions, insertions and deletions, have been reported (3). For instance, proline to leucine mutation at the 102nd position (P102L) ...

show abstract

Section: Discussionsupporting

confidence: 83%

Global transcriptional profiling of the postmortem brain of a patient with G114V genetic Creutzfeldt-Jakob disease

Tian

Chen

et al. 2013

International Journal of Molecular Medicine

View full text Add to dashboard Cite

show abstract

“…Alteration of glycine to a leucine or proline residue introduces a large kinetic barrier to the movement of this area, which prevents formation of PrP Sc . Several mutations have been described to associate with inherited prion disease that occur in or adjacent to the GRR as follows: G114V, A117V, G131V, and S132I (57)(58)(59)(60). Interestingly, each of these mutations is to an amino acid known to be preferentially found in ␤-sheet structures, which may indicate a common method of action (61).…”

Section: Grr Plays a Dominant Role Inmentioning

confidence: 99%

Conservation of a Glycine-rich Region in the Prion Protein Is Required for Uptake of Prion Infectivity

Harrison

Lawson

Coleman

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prion diseases are associated with the misfolding of the endogenously expressed prion protein (designated PrP C ) into an abnormal isoform (PrP Sc ) that has infectious properties. The hydrophobic domain of PrP C is highly conserved and contains a series of glycine residues that show perfect conservation among all species, strongly suggesting it has functional and evolutionary significance. These glycine residues appear to form repeats of the GXXXG protein-protein interaction motif (two glycines separated by any three residues); the retention of these residues is significant and presumably relates to the functionality of PrP C . Mutagenesis studies demonstrate that minor alterations to this highly conserved region of PrP C drastically affect the ability of cells to uptake and replicate prion infection in both cell and animal bioassay. The localization and processing of mutant PrP C are not affected, although in vitro and in vivo studies demonstrate that this region is not essential for interaction with PrP Sc , suggesting these residues provide conformational flexibility. These data suggest that this region of PrP C is critical in the misfolding process and could serve as a novel, species-independent target for prion disease therapeutics.

show abstract

“…Three mutations are notable for their early age of onset, OPRI with insertion of more than five repeats, G114V 27 and H187R. 28 These mutations are associated with early neuropsychiatric symptoms and/or premorbid personality problems.…”

Section: Inherited Prion Diseasementioning

confidence: 99%

“…16 Other clinicians have ascribed psychiatric symptoms in IPD to the early stages of a neurodegenerative disease (eg Rodriguez et al 27 and Laplanche et al 61 ). The presence of personality disorders with such an early onset may indicate a role for the normal function of PrP in the healthy brain that is abrogated by certain mutations.…”

Section: Octapeptide Repeat Insertion (Opri Typically Pq75_p76ins32mentioning

confidence: 99%

Prion disease genetics

2006

View full text Add to dashboard Cite

Prion diseases have stimulated intense scientific scrutiny since it was proposed that the infectious agent was devoid of nucleic acid. Despite this finding, genetics has played a key role in understanding the pathobiology and clinical aspects of prion disease through the effects of a series of polymorphisms and mutations in the prion protein gene (PRNP). The advent of variant Creutzfeldt-Jakob disease has confirmed one of the most powerful human genetic susceptibility factors, as all tested patients have an identical genotype at polymorphic codon 129 of PRNP. This review will also consider the accrued reports of inherited prion disease and attempt a genotype-phenotype correlation. The prospects for detection of novel genetic susceptibility factors using mouse models and human genetic association studies will be explored.

show abstract

A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease

Cited by 47 publications

References 9 publications

Global transcriptional profiling of the postmortem brain of a patient with G114V genetic Creutzfeldt-Jakob disease

Global transcriptional profiling of the postmortem brain of a patient with G114V genetic Creutzfeldt-Jakob disease

Conservation of a Glycine-rich Region in the Prion Protein Is Required for Uptake of Prion Infectivity

Prion disease genetics

Contact Info

Product

Resources

About