Mutations of the Prion Protein Gene

Kovács, Gábor G.; Trabattoni, G; Hainfellner, Johannes A.; Ironside, James W.; Knight, Richard; Budka, Herbert

doi:10.1007/s00415-002-0896-9

Cited by 246 publications

(216 citation statements)

References 122 publications

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“…Cell studies indicate that the instability of the globular fold interferes with GPI-anchor attachment and subsequent cellular processing [155,156]. In vivo, these mutations typically cause a prolonged duration of disease [157] and can lead to abnormal PrP Sc formation [158]. Although correlations between simulation of recPrP and disease are specu-lative, they indicate how MD simulation helps to uncover detailed molecular effects that may be important for the development of familial prion disease.…”

Section: Mutations In the Hydrophobic Corementioning

confidence: 99%

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp

Daggett

2011

Topics in Current Chemistry

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Section: Mutations In the Hydrophobic Corementioning

confidence: 99%

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Kamp

Daggett

2011

Topics in Current Chemistry

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“…25 These descriptions differ from our case that presented with features initially suggesting FTD with parkinsonism, including aphasia, prominent behavioral changes, and severe parkinsonism, and a histologic profile that includes an unusual distribution of GSS type plaques and intense focus of spongiform degeneration in the putamen. Despite these differences, one could argue that this picture may fall within the limits of phenotypic variability associ- ated with prion disease 26 and could, therefore, be observed with any mutation of codon 105. The identification of additional cases of each of these mutations will assist in this regard.…”

Section: Figure 3 Prp Amyloid In Prnp-p105smentioning

confidence: 99%

A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP ^Sc conformation

Tunnell¹,

Wollman²,

Mallik³

et al. 2008

Neurology

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Objective: To define the clinicopathologic, genetic, and pathogenic prion protein (PrP Sc ) characteristics associated with a novel mutation of the prion protein gene (PRNP). Methods:The coding segment of PRNP from the proband and family members was sequenced and the brain of the proband was histologically studied. The Western blot profile of the proteinase K (PK) resistant fraction of PrP Sc , an approximation of its conformation, or "PrP Sc -type," was determined.Results: We detected a novel mutation at codon 105 of PRNP that results in a serine (S) substitution of proline (P) (P105S), in a young woman who developed progressive aphasia, behavioral changes, dementia, and parkinsonism, lasting 10 years to her death. Histopathologic findings included an intense focus of multicentric PrP-plaques within the hippocampus, punctate plaques scattered throughout the cerebellum, and intense spongiform degeneration focally within the putamen, suggesting a variant of Gerstmann-Sträussler-Scheinker syndrome (GSS). However, PrP Sc -typing revealed two PK-resistant PrP Sc fragments (ϳ21 and 26 kDa), a pattern not previously detected in GSS.Conclusions: This mutation is the third sequence variation at codon 105 of PRNP. The unusual phenotype and PrP Sc -type distinguishes this genetic prion disease from typical GerstmannSträussler-Scheinker syndrome and other codon 105 substitutions, suggesting that, in addition to the loss of proline at this position, the PrP Sc conformation and phenotype is dependent on the specific amino acid substitution. Neurology ® 2008;71:1431-1438 GLOSSARY fCJD ϭ familial Creutzfeldt-Jakob disease; FFI ϭ familial fatal insomnia; FTD ϭ frontotemporal dementia; GSS ϭ GerstmannSträussler-Scheinker syndrome; PK ϭ proteinase K.The prion diseases are a family of transmissible neurodegenerative disorders that result from the accumulation of a misfolded isoform (PrP Sc ) of the normal prion protein (PrP C ). 1 Over 30 missense and insertional mutations of the PrP gene (PRNP) lead to the varied expression of three major heritable forms of disease, including familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and familial fatal insomnia (FFI). 2 These prion subtypes are distinguished from each other somewhat by their clinical presentation, but primarily by their associated histopathology. Extensive spongiform degeneration denotes CJD, focal thalamic gliosis and neuronal loss defines FFI, and PrP amyloid plaque deposits characterize GSS. Evidence suggests these phenotypes are enciphered in the conformation of the associated misfolded PrP (PrP Sc ), 3-5 which can be approximated by the Western blot pattern of proteinase K (PK) resistant PrP Sc (rPrP Sc ) within the affected brain. In fCJD and FFI, rPrP Sc displays three fractions with migration rates (M r ) ranging from ϳ19 or 21-33 kiloDaltons (kDa), representing un-, mono-, and di-glycosylated rPrP Sc , whereas a single unglycosylated fragment of ϳ6 -11 kDa is typically detected in GSS. 6

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“…All of these are associated with pathogenic point mutations or octopeptide repeat region insertions into PRNP. The first of these to be identified was the codon P102L mutation in the Gerstmann-Straussler-Scheinker syndrome [14], and currently over 30 PRNP mutations and insertions have been identified, which are associated with a wide clinical range of clinical phenotypes [15]. Familial prion diseases are inherited as autosomal dominant diseases, with a high level of penetrance [4,15].…”

Section: Introductionmentioning

confidence: 99%

“…The first of these to be identified was the codon P102L mutation in the Gerstmann-Straussler-Scheinker syndrome [14], and currently over 30 PRNP mutations and insertions have been identified, which are associated with a wide clinical range of clinical phenotypes [15]. Familial prion diseases are inherited as autosomal dominant diseases, with a high level of penetrance [4,15]. Pathological studies in these rare disorders (which account for only 10% of all human prion diseases) are more restricted than in sporadic CJD, but there is little evidence to indicate that infectivity and/or PrP Sc is present outside the central nervous system [15].…”

Section: Introductionmentioning

confidence: 99%

“…Familial prion diseases are inherited as autosomal dominant diseases, with a high level of penetrance [4,15]. Pathological studies in these rare disorders (which account for only 10% of all human prion diseases) are more restricted than in sporadic CJD, but there is little evidence to indicate that infectivity and/or PrP Sc is present outside the central nervous system [15].…”

Section: Introductionmentioning

confidence: 99%

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Variant Creutzfeldt–Jakob disease and its transmission by blood

Ironside

Head

2003

Journal of Thrombosis and Haemostasis

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Summary. Variant Creutzfeldt–Jakob disease (vCJD) is a novel acquired human prion disease resulting from human exposure to the agent causing bovine spongiform encephalopathy (BSE). vCJD differs from all other human prion diseases in that the disease‐associated form of the prion protein and infectivity are present in lymphoid tissues throughout the body. Lymphoid tissues and lymphocytes are implicated in the peripheral pathogenesis of prion diseases (where infectivity may be detected during the preclinical phase of the illness), giving rise to concerns that blood and blood products may also contain infectivity, thus representing a possible source of iatrogenic spread of vCJD. These concerns have been reinforced by the recent transmission of BSE in an experimental sheep model by blood transfusion from an infected animal in the preclinical phase of the illness. Studies in other animal models suggest that most infectivity in blood may be cell‐associated, with lower levels in the plasma, and there is evidence to indicate that any infectivity present may be reduced during the process of plasma fractionation. At present, the attempts to detect disease‐associated prion protein and infectivity in buffy coat from vCJD patients have been negative, but these studies have been limited in size and in the sensitivity of the detection systems employed. Further studies are required to develop more sensitive means of detection of disease‐associated prion protein in blood; such techniques could also be employed for screening purposes, both individually and to help ascertain more precisely the likely numbers of future cases of vCJD.

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Mutations of the Prion Protein Gene

Cited by 246 publications

References 122 publications

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP ^Sc conformation

Variant Creutzfeldt–Jakob disease and its transmission by blood

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Mutations of the Prion Protein Gene

Cited by 246 publications

References 122 publications

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP Sc conformation

Variant Creutzfeldt–Jakob disease and its transmission by blood

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A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP ^Sc conformation