Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173587 A>C
Position: (GRCh37/hg19):Chr14:73640295 A>C
dbSNP ID: rs63751272
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was described in a British kindred, known as family V. The reported pedigree had 10 affected individuals over four generations, four of whom were known to have autopsy-confirmed AD. The average age of onset in this family was 46, and ranged from 41 to 53 years. The mutation was detected in the four affected members of the family and in one at-risk individual under that age of 50 (Poorkaj et al., 1998).

This mutation was also detected in a French pedigree, known as ALZ 57, with four affected individuals over three generations. In this family onset ranged from 42 to 53, but clinical details were not reported other than that the family had early onset AD (Campion et al., 1999).

In a paper attempting to identify patterns of pathology associated with various familial AD mutations, two brain specimens from patients carrying E120D mutations were analyzed, but it was not indicated whether these individuals carried the A>T or A>C transversion. Age of onset in these individuals was recorded as 34 and 53 years and age at death as 51 and 62 years, respectively. Language loss, seizures, and rigidity were noted as clinical features (Mann et al., 2001).

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

In four cases, neuropathology was consistent with AD.

Biological Effect

This mutant appears to reduce γ-processivity (Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant (nucleotide change unspecified) along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. Secreted levels of total Aβ were reduced. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations, including E120D.

Consistent with these findings, an in vitro assay using purified proteins to test the ability of a the E120D mutant (nucleotide change unspecified) to cleave the APP-C99 substrate revealed decreased Aβ42, and particularly Aβ40, production resulting in a greater than 5-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

Although one study reported mixed results using multiple in silico algorithms to predict the effects of this variant on protein function (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). 

Pathogenicity

Alzheimer's Disease : 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. Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PubMed.
2. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
3. Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T, . Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. Am J Pathol. 2001 Jun;158(6):2165-75. PubMed.
4. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
5. 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.
6. 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
2. CADD v.1.6

Further Reading