Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219185_73219186 GC>TG
Position: (GRCh37/hg19):Chr14:73685893_73685894 GC>TG
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion-Insertion
Expected RNA Consequence: Deletion-Insertion
Expected Protein Consequence: Missense
Codon Change: GCT to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation is a double-point mutation involving two nucleotides within a codon (GCT>TGT). Individuals within the family had variable clinical presentations. Five individuals were affected by Alzheimer’s disease, three of whom had an early onset form. Two individuals had late-onset AD, most likely sporadic, developing at age 66 and 78 years of age, respectively. In the three cases with the early onset form, symptoms started very early. The proband developed progressive emotional lability, depression, and apathy at age 29. He became increasingly forgetful and irritable and developed behavioral disturbances. Severe dementia was present by age 31. Other symptoms included myoclonus, aphasia, visual and auditory hallucinations, and generalized tonic-clonic seizures. A sibling had a similar disease course, starting at age 28; both were confirmed mutation carriers. The mutation is thought to have arisen in their parent, who also had early onset disease (onset at age 35), but genetic analysis was not possible (Devi et al., 2000).

An unrelated individual with presumed AD has been reported, but clinical details were unavailable (Rogaeva et al., 2003).

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

Neuropathology

Postmortem examination of one mutation carrier showed numerous diffuse and neuritic plaques throughout the neocortex, the latter with dense amyloid cores. Neurofibrillary tangles and Hirano bodies were also abundant in the neocortex. Plaques and tangles were found in the amygdala and nucleus basalis. Moderate cell loss and gliosis were evident in the hippocampus, amygdala, and nucleus basalis. The neuropathology was consistent with AD (Devi et al., 2000).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed increased Aβ42 and decreased Aβ40 production, resulting in a greater than 10-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). A434 has been shown to directly interact with APP, forming part of the PAL motif implicated in the recognition of APP by γ-secretase (Sato et al., 2008; Zhou et al., 2019; Jan 2019 news). Computational simulations suggest the A434C mutation reduces the stability of the protein and favors a more open conformation in which the substrate is held more loosely, resulting in imprecise cleavage and earlier release of longer Aβ peptides (Dehury et al., 2020). In some of the simulations, the mutant caused a partial shift of the substrate in the ε-cleavage site, eliminating the hydrogen bond between L432 of PSEN1 and M722 of the C83 APP substrate. The authors note these changes appear to be consistent with an experimentally observed effect on the trimming pathways leading to Aβ (Morishima-Kawashima, 2014).

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.

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. A434C: Variant is in a mutational hot spot, and cryo-EM data and computer simulations 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.

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

Devi G, Fotiou A, Jyrinji D, Tycko B, DeArmand S, Rogaeva E, Song YQ, Medieros H, Liang Y, Orlacchio A, Williamson J, St George-Hyslop P, Mayeux R. Novel presenilin 1 mutations associated with early onset of dementia in a family with both early-onset and late-onset Alzheimer disease. Arch Neurol. 2000 Oct;57(10):1454-7. PubMed.
Rogaeva E, Bergeron C, Sato C, Moliaka I, Kawarai T, Toulina A, Song YQ, Kolesnikova T, Orlacchio A, Bernardi G, St George-Hyslop PH. PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology. 2003 Oct 14;61(7):1005-7. 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.
Sato C, Takagi S, Tomita T, Iwatsubo T. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci. 2008 Jun 11;28(24):6264-71. 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.
Dehury B, Somavarapu AK, Kepp KP. A computer-simulated mechanism of familial Alzheimer's disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase. J Struct Biol. 2020 Dec 1;212(3):107648. Epub 2020 Oct 21 PubMed.
Morishima-Kawashima M. Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase. Front Physiol. 2014;5:463. Epub 2014 Nov 27 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.

Mutations

PSEN1 A434C

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