Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

Smid, Jerusa; Landemberger, Michele Christine; Bahia, Valéria Santoro; Martins, Vilma R.; Nitrini, Ricardo

doi:10.1590/0004-282x20130055

Cited by 6 publications

(4 citation statements)

References 32 publications

(53 reference statements)

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“…He et al reported decreased late-onset risk in Val129 carriers or Val/Val homozygotes but not in early-onset AD [30]. However, the absence of associations between this variant and late-onset AD in two recent studies [31, 32] suggest that rs1799990 is a benign polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Denvir

Neitch

Fan

et al. 2015

JAD

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Background: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations.Objective and Method: In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants.Results: Among the 720 nonsynonymous single nucleotide polymorphisms (SNPs) shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the presenilin 1 (PS1) protein. The presence of this same mutation in a French early-onset Alzheimer’s disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity.Conclusions: Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer’s disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia.

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Section: Discussionmentioning

confidence: 99%

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Denvir

Neitch

Fan

et al. 2015

JAD

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“…Samples were analyzed using denaturing high-performance liquid chromatography. Technical details about this procedure as well as amplification reactions and DNA extraction have been previously described (Castro et al, 2004;Smid et al, 2013).…”

Section: Clinical Investigationmentioning

confidence: 99%

Second-Generation RT-QuIC Assay for the Diagnosis of Creutzfeldt-Jakob Disease Patients in Brazil

Barbosa

Castrillo

Alvim

et al. 2020

Front. Bioeng. Biotechnol.

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The recent development of IQ-CSF, the second generation of real-time quaking-induced conversion (RT-QuIC) using cerebrospinal fluid (CSF), for the diagnosis of Creutzfeldt-Jakob Disease (CJD) represents a major diagnostic advance in the field. Highly accurate results have been reported with encouraging reproducibility among different centers. However, availability is still insufficient, and only a few research centers have access to the method in developing countries. In Brazil, we have had 603 suspected cases of CJD since 2005, when surveillance started. Of these, 404 were undiagnosed. This lack of diagnosis is due, among other factors, to the lack of a reference center for the diagnosis of these diseases in Brazil, resulting in some of these samples being sent abroad for analysis. The aim of this research study is to report the pilot use of IQ-CSF in a small cohort of Brazilian patients with possible or probable CJD, implementing a reference center in the country. We stored CSF samples from patients with possible, probable or genetic CJD (one case) during the time frame of December 2016 through June 2018. All CSF samples were processed according to standardized protocols without access to the clinical data. Eight patients presented to our team with rapidly progressive dementia and typical neurological signs of CJD. We used CSF samples from seven patients with other neurological conditions as negative controls. Five out of seven suspected cases had positive tests; two cases showed inconclusive results. Among controls, there was one false-positive (a CSF sample from a 5-year-old child with leukemia under treatment). The occurrence of a false positive in one of the negative control samples raises the possibility of the presence of interfering components in the CSF sample from patients with non-neurodegenerative pathologies. Our pilot results illustrate the feasibility of having CJD CSF samples tested in Brazilian centers and highlight the importance of interinstitutional collaboration to pursue a higher diagnostic accuracy in CJD in Brazil and Latin America.

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“…Cellular PrP was regarded as a functional receptor of -amyloid peptide (A (Cheng et al, 2016, Kessels et al, 2010, Lauren et al, 2009, which plays a causative role in AD (Gouras et al, 2015, Kellett and Hooper, 2009, Um and Strittmatter, 2013. Studies on PRNP polymorphisms suggested a few mutation sites that affected human susceptibility to AD (Munoz-Nieto et al, 2013, Sassi et al, 2016, Smid et al, 2013. Research in the course of prion diseases revealed several PRNP polymorphisms in mice, which affected the incubation period and the susceptibility to prion diseases (Carlson et al, 1986, Kingsbury et al, 1983, Prusiner, 1982, Westaway et al, 1987, and a few SNPs showed a direct relationship with susceptibility (Lloyd et al, 2004, Moore et al, 1998, Westaway et al, 1987.…”

Section: Introductionmentioning

confidence: 99%

Analysis of experimental mouse PRNP genetic polymorphisms and their susceptibility to prion diseases

Gao

Cai

et al. 2017

IJAR

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Research studies showed that the polymorphisms in prion protein gene (PRNP) were associated with susceptibility to prion diseases in several animals, including humans and mouse. Several mouse strains carried natural PRNP mutations which had been identified and these could provide as animal models for human prion diseases. In this study, the genetic polymorphisms of PRNP in six common mouse strains were investigated. The experimental mice included KM mouse, ICR mouse, DBA mouse, C3H/He mouse, C57BL mouse and BALB mouse. The results showed only one new polymorphism was identified compared with the reference sequence. The identified new mutation site was C564T and it was homozygous, but this locus did not result in amino acid change. Sequence analyses suggested that these six mouse strains were susceptible to prion diseases and are suitable as susceptibility models of prion diseases.

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Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

Cited by 6 publications

References 32 publications

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia

Second-Generation RT-QuIC Assay for the Diagnosis of Creutzfeldt-Jakob Disease Patients in Brazil

Analysis of experimental mouse PRNP genetic polymorphisms and their susceptibility to prion diseases

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