Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198079 A>C
Position: (GRCh37/hg19):Chr14:73664787 A>C
dbSNP ID: rs63750772
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a screen of 25 Japanese families with early onset AD (Kamimura et al., 1998). The proband presented with AD symptoms at age 63. One other family member was reported to be affected. A subsequent study described a Japanese woman carrying the mutation with AD onset at 45 years of age (Islam et al., 2022).

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

Neuropathology
Unknown

Biological function
Although this variant disrupts APP processing, its consequences on Aβ production remain unclear. An in vitro assay using purified proteins to test the ability of E273A PSEN1 to cleave the APP-C99 substrate suggested it generates more Aβ42 than the wild-type protein, resulting in an elevated Aβ42/Aβ40 ratio (Sun et al., 2017). However, a cell-based assay indicated that total Aβ production was decreased in cells expressing the mutant protein, as was specific production of Aβ38, Aβ40, and Aβ42, with the Aβ42/Aβ40 ratio being similar to cells expressing wildtype PSEN1 (Kakuda et al., 2021). Still, the mutation appeared to have a damaging effect as it increased levels of the toxic peptide Aβ43. Analyses of the short peptides generated by several AD-associated PSEN1 mutants suggested Aβ43 may be generated from Aβ48, rather than the canonical Aβ49 precursor. Interestingly, increased Aβ43 levels and increased production by the alternate Aβ48 pathway correlated with younger ages at disease onset.

In addition, presenilins have been reported to act as passive calcium leak channels in the endoplasmic reticulum, and E273A abolished this function in vitro and in cultured cells (Nelson et al., 2007). Also, in one carrier with an APOE3/3 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to a disruption of PSEN1’s proposed role in ApoE secretion.

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). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. E273A: Although results varied between assays, they were all supportive of a damaging effect.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 04 Mar 2022

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References

Paper Citations

Kamimura K, Tanahashi H, Yamanaka H, Takahashi K, Asada T, Tabira T. Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
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.
Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
Nelson O, Tu H, Lei T, Bentahir M, de Strooper B, Bezprozvanny I. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. J Clin Invest. 2007 May;117(5):1230-9. Epub 2007 Apr 12 PubMed.
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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 E273A

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