Childhood Onset in Familial Prion Disease With a Novel Mutation in the PRNP Gene

Rogaeva, Ekaterina; Zadikoff, Cindy; Ponesse, Jonathan; Schmitt‐Ulms, Gerold; Kawarai, Toshitaka; Sato, Christine; Salehi-Rad, Shabnam; George-Hyslop, Peter St; Lang, Anthony E.

doi:10.1001/archneur.63.7.1016

Cited by 19 publications

(9 citation statements)

References 18 publications

(13 reference statements)

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“…24 Although the histologic profile of P105T has not been described, ataxia and dementia were the principal clinical features reported. 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.…”

Section: Figure 3 Prp Amyloid In Prnp-p105scontrasting

confidence: 95%

“…A leucine substitution (P105L) was initially reported in several Japanese families [22][23][24] and a threonine substitution (P105T) was subsequently detected in a Canadian family. 25 The polymorphic codon 129, which is known to affect prion disease phenotype, is Val on the mutated allele in both P105S and P105L, but Met on the P105T allele. The clinicopathologic picture most associated with P105L has been the development of spastic paraparesis in the absence of prominent ataxia, the diffuse deposition of GSS-type plaques, and the absence of spongiform degeneration.…”

Section: Figure 3 Prp Amyloid In Prnp-p105smentioning

confidence: 99%

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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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Section: Figure 3 Prp Amyloid In Prnp-p105scontrasting

confidence: 95%

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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“…Thus, it seems likely that the primary effect of the leucine residues was conformational. At the same time, we note that mutations of Pro-105 to serine or threonine have also been linked to prion disease in humans (38,39). These latter substitutions at Pro-105 would increase side chain hydrogen-bonding capacity rather than hydrophobicity.…”

Section: Discussionmentioning

confidence: 70%

“…The fact that mutations of Pro-102 and Pro-105 are linked to PrP D accumulation and devastating human prion disease (38,39) suggests that these prolines protect against the pathologic misfolding of PrP C . Our current demonstration that substitution of these proline residues with the disease-linked leucines accelerates PrP amyloid formation of N-terminally extended PK-resistant amyloid cores reminiscent of PrP D is consistent with this possibility.…”

Section: Discussionmentioning

confidence: 99%

Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation

Kraus

Anson

Raymond

et al. 2015

Journal of Biological Chemistry

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Background:We investigated how pathogenic prion protein mutations P102L and P105L lead to misfolding. Results: Mutations of these proline and adjacent lysine residues accelerated in vitro formation of amyloid with properties reminiscent of PrP Sc . Conclusion: Specific proline and lysine residues might delay spontaneous prion disease by hindering PrP conversion into amyloid. Significance: These findings suggest mechanisms for genetic prion diseases.

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“…To date, more than 30 mutations of PRNP have been found in the open reading frame (ORF) of this gene (3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). These mutations are the only cause of familial prion diseases, which include familial CJD, GSS, and FFI (31, 32, 33).…”

Section: Introductionmentioning

confidence: 99%

Genetic Studies in Human Prion Diseases

Jeong

Kim

2014

J Korean Med Sci

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Human prion diseases are fatal neurodegenerative disorders that are characterized by spongiform changes, astrogliosis, and the accumulation of an abnormal prion protein (PrPSc). Approximately 10%-15% of human prion diseases are familial variants that are caused by pathogenic mutations in the prion protein gene (PRNP). Point mutations or the insertions of one or more copies of a 24 bp repeat are associated with familial human prion diseases including familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. These mutations vary significantly in frequency between countries. Here, we compare the frequency of PRNP mutations between European countries and East Asians. Associations between single nucleotide polymorphisms (SNPs) of several candidate genes including PRNP and CJD have been reported. The SNP of PRNP at codon 129 has been shown to be associated with sporadic, iatrogenic, and variant CJD. The SNPs of several genes other than PRNP have been showed contradictory results. Case-control studies and genome-wide association studies have also been performed to identify candidate genes correlated with variant and/or sporadic CJD. This review provides a general overview of the genetic mutations and polymorphisms that have been analyzed in association with human prion diseases to date.Graphical Abstract

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Childhood Onset in Familial Prion Disease With a Novel Mutation in the PRNP Gene

Cited by 19 publications

References 18 publications

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

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

Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation

Genetic Studies in Human Prion Diseases

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Childhood Onset in Familial Prion Disease With a Novel Mutation in the PRNP Gene

Cited by 19 publications

References 18 publications

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

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

Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation

Genetic Studies in Human Prion Diseases

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Product

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

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