Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73173687 T>A
Position: (GRCh37/hg19):Chr14:73640395 T>A
dbSNP ID: rs63750588
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to AAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a 47-year-old Japanese woman who developed presenile dementia in her 40s, preceded by spastic paraparesis in her 30s (Hattori et al., 2004). Her mother presented with spastic paraparesis in her 40s, followed by dementia in her mid-60s. The mutation was found in the proband, but not in an unaffected older sister, 103 healthy controls, 15 patients with early onset AD without spastic paraparesis, 50 patients with late-onset AD, and seven patients with familial spastic paraparesis without dementia. Although the exact age of the unaffected sister was unavailable, she was at least a decade past the proband's age at onset.

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

Neuropathology

Neuropathological data for this mutation are unavailable. MRI and SPECT imaging of the proband’s brain revealed atrophy and hypoperfusion in occipito-parietal areas, as well as in internal temporal lobe areas, including the hippocampus. In addition, Aβ42 levels were reduced in CSF, while total tau and phospho-tau levels were increased.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate suggests it drastically reduces Aβ40 and Aβ42 production, with Aβ40 being undetectable, and abrogates endopeptidase activity (Sun et al., 2017). As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, Y154 appears to help stabilize the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019 news).

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 : Pathogenic

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

Comments

1. • Andre Delacourte
     Inserm
   • Posted: 23 Sep 2004
   • Paper: A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis.

   This paper shows, one more time, that the very first clinical symptoms of FAD with early onset are not necessarily linked to memory.

   View all comments by Andre Delacourte

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References

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Hattori S, Sakuma K, Wakutani Y, Wada K, Shimoda M, Urakami K, Kowa H, Nakashima K. A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis. Neurosci Lett. 2004 Sep 30;368(3):319-22. PubMed.
2. 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.
3. 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.
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