A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism

Gatto, Emilia; Rojas, Galeno; Nemirovsky, Sergio I.; Prat, Gustavo Da; Persi, Gabriel; Cesarini, Martin; Etcheverry, José Luis; Rojas, Natalia González; Parisi, Virginia; Córdoba, Manuel Benabent Fernández de; Sevlever, Gustavo; Allegri, Ricardo; Turjanski, Adrián

doi:10.1016/j.parkreldis.2020.06.005

Cited by 14 publications

(16 citation statements)

References 15 publications

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“…PS2 Gly34Ser was not detected in any individual without AD among the family members. Interestingly, PS1 Arg41Ser was identified in patients with early-onset PD [ 33 ]. Pathogenic PSEN mutations were mostly found in transmembrane regions.…”

Section: Discussionmentioning

confidence: 99%

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Shim

Kang

Bae

et al. 2022

IJMS

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Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.

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Section: Discussionmentioning

confidence: 99%

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Shim

Kang

Bae

et al. 2022

IJMS

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“…Besides their established role in mediating the formation of Aβ peptide, more recently mutant PS1 has been shown to impair numerous cellular functions, such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism 60 . Interestingly, a novel PSEN1 mutation was recently identified as the likely cause for early‐onset parkinsonism 61 …”

Section: Discussionmentioning

confidence: 99%

“…60 Interestingly, a novel PSEN1 mutation was recently identified as the likely cause for early-onset parkinsonism. 61…”

Section: Insights Into the Differentially Expressed Circrna Genesmentioning

confidence: 99%

Differentially Expressed Circular RNAs in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease

et al. 2021

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Background New noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of Parkinson's disease (PD) diagnosis are urgently needed. Circular RNAs (circRNAs) are stable noncoding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function. Objectives Τhe aims of this study were to identify differentially expressed circRNAs in blood mononuclear cells of patients with idiopathic PD and explore the competing endogenous RNA networks affected. Methods Eighty‐seven circRNAs were initially selected based on relatively high gene expression in the human brain. More than half of these were readily detectable in blood mononuclear cells using real‐time reverse transcription‐polymerase chain reaction. Comparative expression analysis was then performed in blood mononuclear cells from 60 control subjects and 60 idiopathic subjects with PD. Results Six circRNAs were significantly down‐regulated in patients with PD. The classifier that best distinguished PD consisted of four circRNAs with an area under the curve of 0.84. Cross‐linking immunoprecipitation‐sequencing data revealed that the RNA‐binding proteins bound by most of the deregulated circRNAs include the neurodegeneration‐associated FUS, TDP43, FMR1, and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs have the Gene Ontology categories “protein modification” and “transcription factor activity” mostly enriched. Conclusions This is the first study that identifies specific circRNAs that may serve as diagnostic biomarkers for PD. Because they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected. © 2021 Biomedical Research Foundation, Academy of Athens. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…Parkinsonism is part of the PSEN1-associated phenotype; however, the occurrence of parkinsonism as an early sign is uncommon. We reviewed six reports (including our study) of seven patients with PSEN1 mutations and a disease onset symptom of EOP (Table 1) [3,[8][9][10][11]. The age at disease onset ranged from 25 to 42 years.…”

Section: Discussionmentioning

confidence: 99%

A heterozygous de novo PSEN1 mutation in a patient with early-onset parkinsonism

et al. 2021

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Background Mutations in presenilin 1 (PSEN1) are the most common known genetic cause of early-onset Alzheimer's disease. Patients with PSEN1 mutations exhibit broad phenotypes. Here, we report clinical, neuroimaging and genetic findings in a patient with a de novo mutation in PSEN1 (c.697A > G, p.M233V) presenting with early-onset parkinsonism as the initial and primary symptom. Methods We recruited a family with one affected patient with early-onset parkinsonism. The patient underwent comprehensive neurological examination and imaging evaluation. Whole genome sequencing was performed for the proband. ResultsThe patient presented with parkinsonism and mild cognitive impairment. He had a good response to levodopa. Brain MRI evaluation showed atrophy of the bilateral frontotemporal lobe and hippocampus. 18 F-fluorodeoxyglucose-positron emission tomography (PET) and 11 C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane-PET showed decreased metabolism and dopamine transporter distribution in the bilateral putamen and caudate nucleus. 11 C-Pittsburgh compound B -PET showed β-amyloid protein deposition. Genetic analysis identified a heterozygous de novo variant in PSEN1 (c.697A > G, p.M233V). Conclusions Screening for PSEN1 variations should be considered in patients with levodopa-responsive early-onset parkinsonism.

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A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism

Cited by 14 publications

References 15 publications

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

Differentially Expressed Circular RNAs in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease

A heterozygous de novo PSEN1 mutation in a patient with early-onset parkinsonism

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