Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73170956_73170961 ATCATG >------
Position: (GRCh37/hg19):Chr14:73637664_73637669 ATCATG >------
dbSNP ID: rs63750307
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: ATC.ATG to ---.---
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This hexanucelotide deletion was identified in the proband of a large Scottish family known as EB with five affected members across three generations. Affected family members presented first with spastic paraparesis, followed by cognitive decline attributed to early onset Alzheimer's disease. The mean age of onset for spastic paraparesis was 36 years (range: 34 to 38 years). This mutation involves deletion of codons 83 and 84 resulting in removal of isoleucine and methionine (Houlden et al., 2000, Steiner et al., 2001). Co-segregation with disease was not established; genetic analysis was limited to the proband.

This variant was absent from the gnomAD variant database (May 2021). 

Neuropathology

This mutation is associated with cotton-wool plaques similar to what was described in the family FINN2, whose affected members carry the ΔE9Finn mutation (PS1del9) (Crook et al., 1998). Plaques appeared in the neuropil as round, eosinophilic, and Aβ-positive structures often larger than 100 μm in diameter. Although Aβ-positive, they were generally noncongophilic, suggesting a lack of amyloid. Although widespread in the brain parenchyma, they were most abundant in the neocortex, hippocampus, and striatum. Cerebral amyloid angiopathy, neurofibrillary tangles, and neuropil threads were also noted (Steiner et al., 2001).

Biological Effect

I83_M84del is a hexanucleotide deletion resulting in the loss of two adjacent amino acids. Cultured H4 glioma cells expressing the mutant protein secreted very high levels of Aβ42 and had an elevated Aβ42/Aβ40 ratio compared to cells transfected with wild-type PSEN1 (Houlden et al., 2000). A similar elevation of the Aβ42/Aβ40 ratio was seen in HEK-293 cells expressing APP with the Swedish mutation.

A subsequent study that surveyed additional Aβ peptides in human embryonic kidney cells expressing this variant and lacking endogenous PSEN1 and PSEN2, found that, in addition to elevating the Aβ42/Aβ40 ratio, the mutant protein reduced the Aβ37/Aβ42 ratio (Liu et al., 2022). Of note, although both Aβ42/Aβ40 and Aβ37/Aβ42 proved useful for distinguishing control versus AD samples, Aβ37/Aβ42 outperformed Aβ42/Aβ40. In this same study, the toxic Aβ43 peptide was found to be increased, as well as both Aβ40 and Aβ42. Although an in vitro study using isolated proteins reported an abrogation of Aβ40 production and a drastic reduction in Aβ42 production (Sun et al., 2017), the biological significance of this assay is unclear given that nearly half of 138 mutant recombinant PSEN1 proteins tested generated less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

As revealed by experiments using Caenorhabditis elegans, this mutation also disrupts the processing of the γ-secretase substrate Notch (Steiner et al., 2001).

Multiple in silico algorithms predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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. Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, Wood NW, Kumar-Singh S, Geddes J, Swash M, Scaravilli F, Holton JL, Lashley T, Tomita T, Hashimoto T, Verkkoniemi A, Kalimo H, Somer M, Paetau A, Martin JJ, Van Broeckhoven C, Golde T, Hardy J, Haltia M, Revesz T. Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000 Nov;48(5):806-8. PubMed.
2. Steiner H, Revesz T, Neumann M, Romig H, Grim MG, Pesold B, Kretzschmar HA, Hardy J, Holton JL, Baumeister R, Houlden H, Haass C. A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques. J Biol Chem. 2001 Mar 9;276(10):7233-9. Epub 2000 Nov 17 PubMed.
3. Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Pöyhönen M, Kucera S, Haltia M. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
4. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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. 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.
7. 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.

Other Citations

1. ΔE9Finn

External Citations

1. gnomAD variant database

Further Reading

No Available Further Reading