Hypokinesia and presenile dementia in a Dutch family with a novel insertion in the prion protein gene

Gool, W. A. Van; Hensels, G. W.; Hoogerwaard, E. M.; Wiezer, J. H. A.; Wesseling, Pieter; Bolhuis, P. A.

doi:10.1093/brain/118.6.1565

Cited by 40 publications

(3 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It may also be related to amyloid formation, as patients with 8 or 9 extra repeats often show a GSS disease phenotype with numerous multicentric plaques [5, 9, 15, 26], whereas patients with OPRI mutations consisting of less than 5 extra repeats present in a way similar to the typical presentation of CJD. Nevertheless, the exact mechanism of amyloid formation in prion diseases still remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature

et al. 2010

View full text Add to dashboard Cite

Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrPSc) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2–R2–R2–R2–R3g–R2–R2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrPSc in both patients and detected a smaller ~8 kDa PrPSc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype–phenotype correlations in inherited prion diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature

et al. 2010

View full text Add to dashboard Cite

show abstract

“…1) is thought to be mostly responsible for conferring PrP with its neurotoxic and amyloidogenic properties (Selvaggini et al 1993;De Gioia et al 1994); however, the copper-binding ORs have also been implicated in misfolding. It has been clearly demonstrated that extra copies of the repeats, from one to nine additional inserts, can trigger spontaneous disease in humans (Collinge et al , 1992Owen et al 1989Owen et al , 1991Goldfarb et al 1991;Laplanche et al 1995Laplanche et al , 1999van Gool et al 1995;Campbell et al 1996;Cochran et al 1996;Windl et al 1999). In transgenic mouse experiments, OR-deletion mutants of PrP are still susceptible to disease, but the duration until disease signs appear is increased (Flechsig et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Can copper binding to the prion protein generate a misfolded form of the protein?

et al. 2009

View full text Add to dashboard Cite

The native prion protein (PrP) has a two domain structure, with a globular folded alpha-helical C-terminal domain and a flexible extended N-terminal region. The latter can selectively bind Cu(2+) via four His residues in the octarepeat (OR) region, as well as two sites (His96 and His111) outside this region. In the disease state, the folded C-terminal domain of PrP undergoes a conformational change, forming amorphous aggregates high in beta-sheet content. Cu(2+) bound to the ORs can be redox active and has been shown to induce cleavage within the OR region, a process requiring conserved Trp residues. Using computational modeling, we have observed that electron transfer from Trp residues to copper can be favorable. These models also reveal that an indole-based radical cation or Cu(+) can initiate reactions leading to protein backbone cleavage. We have also demonstrated, by molecular dynamics simulations, that Cu(2+) binding to the His96 and His111 residues in the remaining PrP N-terminal fragment can induce localized beta-sheet structure, allowing us to suggest a potential mechanism for the initiation of beta-sheet misfolding in the C-terminal domain by Cu(2+).

show abstract

“…The incidence is not clear but was estimated to be 1 to 10 per 100 million. GSS has been associated with the following missense mutations: P102L [ 46 ]; P105L [ 47 ]; A117V [ 48 ]; F198S [ 49 ]; D202N, Q212P [ 50 ]; Q217R [ 49 ], and in some cases of octapeptide repeat insertions (OPRI), especially those with larger inserts (approximately 192 bp) [ 51 , 52 , 53 ].…”

Section: Polymorphisms and Mutations In The Prnp mentioning

confidence: 99%

The Structure of Human Prions: From Biology to Structural Models—Considerations and Pitfalls

Acevedo-Morantes

Wille

2014

Viruses

View full text Add to dashboard Cite

Prion diseases are a family of transmissible, progressive, and uniformly fatal neurodegenerative disorders that affect humans and animals. Although cross-species transmissions of prions are usually limited by an apparent “species barrier”, the spread of a prion disease to humans by ingestion of contaminated food, or via other routes of exposure, indicates that animal prions can pose a significant public health risk. The infectious agent responsible for the transmission of prion diseases is a misfolded conformer of the prion protein, PrPSc, a pathogenic isoform of the host-encoded, cellular prion protein, PrPC. The detailed mechanisms of prion conversion and replication, as well as the high-resolution structure of PrPSc, are unknown. This review will discuss the general background related to prion biology and assess the structural models proposed to date, while highlighting the experimental challenges of elucidating the structure of PrPSc.

show abstract

Hypokinesia and presenile dementia in a Dutch family with a novel insertion in the prion protein gene

Abstract: SummaryThe

Cited by 40 publications

References 17 publications

A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature

A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature

Can copper binding to the prion protein generate a misfolded form of the protein?

The Structure of Human Prions: From Biology to Structural Models—Considerations and Pitfalls

Contact Info

Product

Resources

About