Overview

Pathogenicity: Parkinson's Disease : Not Classified
Clinical Phenotype: Parkinson's Disease
Position: (GRCh38/hg38):Chr14:73170832 A>T
Position: (GRCh37/hg19):Chr14:73637540 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGA to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in a 46-year-old Argentinian woman diagnosed with early onset Parkinson’s disease (PD) at age 35 (Gatto et al., 2020). Her initial symptoms were asymmetric resting tremor, bradykinesia, and rigidity of the left side of her body. Parkinsonism was responsive to L-dopa treatment, and progressed, including the development of pain and dyskinesia. The woman also suffered from iron deficiency and anemia since childhood. Of note, neither memory impairment nor dementia were reported. Two neuropsychological examinations showed only mild, non-amnestic cognitive impairment at age 46.

After finding no mutations in seven PD-associated genes, the authors used whole-exome sequencing followed by web-based filters to prioritize potential pathogenic variants. PSEN1 R41S was identified as the best candidate to account for the phenotype, given that R41 is highly conserved in vertebrates, a healthy sibling did not carry the mutation, and the R41S substitution was absent from the variant databases dbSNP and gnomAD. Furthermore, neighboring variants were found to be extremely rare. Although the affected woman’s parents were unavailable for genotyping, the mutation was assumed to have arisen de novo, since there was no family history of neurodegenerative disorders.

Neuropathology
Neuropathological data are unavailable, but a brain MRI scan showed moderate atrophy of the frontal cortex. Interestingly, no clear signs of AD-related pathology were detected. A mild increase in phosphorylated tau was found in cerebrospinal fluid, but levels of Aβ and total tau were normal. Also, PiB-PET failed to reveal cortical amyloid deposition, and FDG-PET showed mild hypometabolism in the left lateral temporal lobe, a pattern more aligned with normal aging than with AD.

Biological Effect

The biological effect of this mutation is unknown, but two algorithms, PhyloP and PhastCons, indicated the position is highly conserved amongst vertebrates.

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021).

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References

Paper Citations

1. Gatto EM, Rojas GJ, Nemirovsky SI, Da Prat G, Persi G, Cesarini M, Etcheverry JL, Rojas NG, Parisi V, Cordoba M, Sevlever G, Allegri RF, Turjanski AG. A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism. Parkinsonism Relat Disord. 2020 Aug;77:21-25. Epub 2020 Jun 17 PubMed.
2. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading

No Available Further Reading