Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73206388 A>C
Position: (GRCh37/hg19):Chr14:73673096 A>C
dbSNP ID: rs63750298
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Missense; Deletion
Codon Change: ACA to CCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

This mutation has been found in several individuals presenting with motor impairment years before the onset of cognitive decline due to Alzheimer's disease. It was initially identified in a French individual who was referred to a neurologist at age 33 for progressive motor impairment, including a spastic gait. Ten years later, he required a wheelchair and had severe dysarthria (difficulty speaking due to impairment of speech producing muscles). He had also developed dementia with prominent frontal lobe dysfunction. Segregation with disease could not be determined due to lack of DNA from relatives (Dumanchin et al., 2006).

This variant was also identified in a Greek individual who presented with pure spastic paraplegia at 30 years of age (Chelban et al., 2021). Three years later, the patient developed severe, fast cognitive decline. Similarly, his mother had spastic paraperesis in her 30s with no cognitive impairment at onset, and then went through severe cognitive decline and died before age 40. 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

A brain biopsy of the Greek patient revealed amyloid deposition with diffuse cortical plaques (Chelban et al., 2021). In the French patient, MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding (Dumanchin et al., 2006). 

Biological Effect

The mutant protein mediated normal active γ-secretase reconstitution, but it destabilized γ-secretase-APP/Aβn interactions during proteolysis, enhancing production of longer Aβ peptides as assessed by cellular and in vitro assays (Chelban et al., 2021). Consistently, when expressed in HEK293 cells, it increased Aβ40 and Aβ42 measured in the conditioned media. Although the concentrations of both peptides increased, the increase was greater for Aβ42 and the overall ratio of Aβ42/Aβ40 was elevated compared to that of cells expressing wild-type PSEN1 (Dumanchin et al., 2006). An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, also revealed an increase in the Aβ42/Aβ40 ratio, but it generated dramatically less Aβ42 than the wild-type protein and abolished Aβ40 production (Sun et al., 2017).

This point mutation has also been shown to affect exon 9 splicing, leading to the exclusion of exon 9 in about 5 percent of transcripts (Dumanchin et al., 2006).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
2. Chelban V, Breza M, Szaruga M, Vandrovcova J, Murphy D, Lee CJ, Alikhwan S, Bourinaris T, Vavougios G, Ilyas M, Halim SA, Al-Harrasi A, Kartanou C, Ronald C, Blumcke I, Alexoudi A, Gatzonis S, Stefanis L, Karadima G, Wood NW, Chávez-Gutiérrez L, Hardy J, Houlden H, Koutsis G. Spastic paraplegia preceding PSEN1-related familial Alzheimer's disease. Alzheimers Dement (Amst). 2021;13(1):e12186. Epub 2021 May 2 PubMed.
3. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
4. 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading