A new mutation in the prion protein gene: A patient with dementia and white matter changes

Harten, Barbera van; Gool, Willem A. van; Langen, van Irene; Deekman, J.M.; Meijerink, P.H.S.; Weinstein, H. C.

doi:10.1212/wnl.55.7.1055

Cited by 18 publications

(11 citation statements)

References 8 publications

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“…19 20 Van Harten et al also described a patient with a two-octapeptide repeat insertion with atypical dementia in The Netherlands. 20 We could not find a link between the two Dutch patients within six generations.…”

Section: Discussionmentioning

confidence: 66%

“…19 The nucleotide sequence in the third and fourth octapeptide repeat in our patient also changed, and was identical to that described by van Harten et al in a patient of Dutch origin (R1 R2 R2a R2 R2a R2a R4). 20 The normal order is R1 (the nonapeptide repeat) R2 R2 R3 R4. The patient was heterozygous for the polymorphic PRNP codon 129, carrying the valine (V) allele on the chromosome with the octapeptide repeat insertion, which is identical to the disease haplotype in the patient described by Van Harten.…”

Section: Mutation Screening and Clinical Phenotypementioning

confidence: 99%

“…The patient was heterozygous for the polymorphic PRNP codon 129, carrying the valine (V) allele on the chromosome with the octapeptide repeat insertion, which is identical to the disease haplotype in the patient described by Van Harten. 20 Genealogical data from our patient and the patient described by Van Harten et al were collected using the municipal registers. We were able to trace back the ancestors of both patients for six generations, until 1780, but it was not possible to link both patients to a common ancestor within these six generations.…”

Section: Mutation Screening and Clinical Phenotypementioning

confidence: 99%

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Octapeptide repeat insertions in the prion protein gene and early onset dementia

Croes

Theuns²,

Houwing-Duistermaat³

et al. 2004

Journal of Neurology, Neurosurgery & Psychiatry

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Objectives: The most common familial early onset dementia mutations are found in the genes involved in Alzheimer's disease; the amyloid precursor protein (APP) and the presenilin 1 and 2 (PSEN1 and 2) genes; the prion protein gene ( PRNP) may be involved. Methods: Following identification of a two-octapeptide repeat insertion in PRNP, we conducted a meta-analysis to investigate the relation of number of PRNP octapeptide repeats with age at disease onset and duration of illness; identifying 55 patients with PRNP octapeptide repeat insertions. We used a linear mixed effects model to assess the relation of number of repeats with age at disease onset, and studied the effect of the number of inserted octapeptide repeats on disease duration with a Cox proportional hazards regression analysis. Results: We found an increasing number of repeats associated with younger age at onset (p< 0.001). Duration of the disease decreased significantly with the length of the octapeptide repeat (p< 0.001) when adjusting for age at onset. Conclusions: Our findings show significant inverse associations of the length of the PRNP octapeptide repeat with age at disease onset and disease duration in the spongiform encephalopathies

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Section: Discussionmentioning

confidence: 66%

Section: Mutation Screening and Clinical Phenotypementioning

confidence: 99%

Section: Mutation Screening and Clinical Phenotypementioning

confidence: 99%

See 1 more Smart Citation

Octapeptide repeat insertions in the prion protein gene and early onset dementia

Croes

Theuns²,

Houwing-Duistermaat³

et al. 2004

Journal of Neurology, Neurosurgery & Psychiatry

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“…His mother also carried the same mutation, but developed a slowly progressive dementia, with onset at age 75 and disease duration longer than 13 years [Goldfarb et al, 1993]. Two apparently non-related Dutch patients were also reported with this mutation [Croes et al, 2004;van Harten et al, 2000]. One (129MV) had onset at age 59 and was mute ten years later [Croes et al, 2004].…”

Section: -Oprimentioning

confidence: 99%

Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature

Takada

Kim

Cleveland

et al. 2016

American J of Med Genetics Pt B

101

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Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.

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“…The connection between the involvement of copper and prion disease is not clear-cut, as mice treated with a Cu 21 specific chelator (D-penicillamine) demonstrated a delayed onset of disease (20). Although the N-terminal portion of PrP has been shown to be proteolytically removed in the proteaseresistant form (21), there is evidence that individuals with additional OR sites, arising from spontaneous gene mutation, for example, have an increased susceptibility to prion diseases (22)(23)(24)(25). The prevalence of OR insertion mutations in disease cases implies that such alterations are a risk factor for developing inherited prion disease (i.e., without extraneous influence from infectious PrP particles).…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of Two Tandem Octarepeats from the Mammalian Prion Protein: Fully Cu2+-bound and Metal-Free Forms

Pushie

Vogel

2007

Biophysical Journal

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Molecular dynamics simulations have been conducted on a model fragment (Ac-PHGGGWGQPHGGGW-NH(2)) of the prion protein octarepeat domain, both in the Cu(2+)-bound and metal-free forms. The copper-bound models are based on the consensus structure of the core Cu(2+)-binding site of an individual octarepeat, relevant to the fully Cu(2+)-occupied prion protein octarepeat region. The model peptides contain Cu(2+) bound through a His imidazole ring and two deprotonated amide N-atoms in the peptide backbone supplied by the following two Gly residues. Both the copper-bound and metal-free models have been simulated with the OPLS all-atom force field with the GROMACS molecular dynamics package. These simulations, with two tandem copper-binding sites, represent the minimum model necessary to observe potential structuring between the copper-binding sites in the octarepeat region. The GWGQ residues constitute a flexible linker region that predominantly adopts a turn, serving to bring adjacent His residues into close proximity. The consequent formation of stable structures demonstrates that the copper-bound octarepeat region allows the copper-coordinating sites to come into van der Waals contact, packing into particular orientations to further stabilize the bend in the GWGQ linker region.

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A new mutation in the prion protein gene: A patient with dementia and white matter changes

Cited by 18 publications

References 8 publications

Octapeptide repeat insertions in the prion protein gene and early onset dementia

Octapeptide repeat insertions in the prion protein gene and early onset dementia

Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature

Molecular Dynamics Simulations of Two Tandem Octarepeats from the Mammalian Prion Protein: Fully Cu2+-bound and Metal-Free Forms

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