Overview

Pathogenicity: Dementia : Not Classified
Clinical Phenotype: Dementia with Lewy Bodies
Position: (GRCh38/hg38):Chr14:73198084 G>T
Position: (GRCh37/hg19):Chr14:73664792 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to TCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant was found in a 77-year-old Caucasian woman in New Zealand with clinical features of dementia with Lewy bodies (Joshi et al., 2021). The woman had a four-year history of progressive impairment of memory, speech, and ability to do calculations. She also had tremor of the hands and a disorder of rapid eye movement sleep. Her mother had developed dementia at about age 60 and two sisters developed dementia and parkinsonism in their 70s.

The authors identified the A275S heterozygote variant after screening loci in 25 dementia- and Parkinson-related genes. In addition to A275S, they found a heterozygote variant in the PLA2G6 gene (R475Q), and determined the proband had an APOE3/E4 genotype. Genetic data were available only for the proband.

The A275S variant was absent from the gnomAD database.

Neuropathology
Neuropathological data are unavailable. An MRI scan of the proband revealed mild generalized atrophy, and a florbetaben PET scan showed bilateral cortical amyloid accumulation (Joshi et al., 2021). Of note, hippocampal atrophy was undetectable. Also of note, a brain scan to assess dopamine transporter status was normal, a finding inconsistent with dementia with Lewy bodies.

Biological Effect
The biological effect of this variant is unknown, but it is found in a highly conserved region and in silico algorithms predicted a damaging effect, with a PHRED-scaled CADD score of 27.2 (Joshi et al., 2021), and another missense mutation at this site, A275V, has been classified as pathogenic for Alzheimer's disease.

The authors noted that, although the PLA2G6 variant R475Q is considered of uncertain significance, it may contribute to the observed phenotype given that PLA2G6 has been reported to accumulate in Lewy bodies (Miki et al., 2017).

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References

Mutations Citations

1. PSEN1 A275V

Paper Citations

1. Joshi P, Gardner M, Lintott C, Anderson T. Novel Presenilin-1 Mutation (Ala275Ser) Associated With Clinical Features of Dementia With Lewy Bodies. Alzheimer Dis Assoc Disord. 2021 Mar 23; PubMed.
2. Miki Y, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K. PLA2G6 accumulates in Lewy bodies in PARK14 and idiopathic Parkinson's disease. Neurosci Lett. 2017 Apr 3;645:40-45. Epub 2017 Feb 14 PubMed.

Further Reading

No Available Further Reading