Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173644 G>A
Position: (GRCh37/hg19):Chr14:73640352 G>A
dbSNP ID: rs63750522
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first reported in a family known as Duke AD family 1674. This family previously had been shown to have early onset Alzheimer’s disease linked to chromosome 14. The M139I mutation was detected in two affected family members and was absent in two unaffected family members (Boteva et al., 1996).

The mutation was also found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband carried, not only the PSEN1 M139I mutation, but an APP variant, D332G, which had not been previously reported in patients with familial AD and was classified as of "uncertain significance." The PSEN1 M139I mutation was absent from three population-based databases, 1000 Genomes Project, ExAC, and gnomAD.

Neuropathology

Brain tissue from two cases carrying the M139I mutation was examined by immunohistochemistry; however, it was not clear in this report whether the individuals carried the G>A or G>C version of this mutation (Mathews et al., 2000). In contrast to the eight other presenilin mutations examined, pyramidal neurons in M139I brains showed neurofibrillary tangles labeled with PSEN1 antibodies. The authors speculated that the presenilin protein might become mislocalized during neurodegeneration, as the expression level of the protein and its processing were comparable to control brains and those with sporadic AD.

Biological Effect

In vitro, the M139I mutation (nucleotide change unspecified) increases the Aβ42/Aβ total ratio in COS-1 cells co-transfected with APP695 (Murayama et al., 1999). Moreover, the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021), although some in silico analyses yielded conflicting results (Jiang et al., 2019, Xiao et al., 2021). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

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.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M139I (G>A): Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. M139I (G>A): At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 22 Feb 2022

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References

News Citations

Paper Citations

Boteva K, Vitek M, Mitsuda H, de Silva H, Xu PT, Small G, Gilbert JR. Mutation analysis of presenillin 1 gene in Alzheimer's disease. Lancet. 1996 Jan 13;347(8994):130-1. PubMed.
Jiang B, Zhou J, Li HL, Chen YG, Cheng HR, Ye LQ, Liu DS, Chen DF, Tao QQ, Wu ZY. Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
Mathews PM, Cataldo AM, Kao BH, Rudnicki AG, Qin X, Yang JL, Jiang Y, Picciano M, Hulette C, Lippa CF, Bird TD, Nochlin D, Walter J, Haass C, Lévesque L, Fraser PE, Andreadis A, Nixon RA. Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease. Mol Med. 2000 Oct;6(10):878-91. PubMed.
Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. 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.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Mutations

PSEN1 M139I (G>A)

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