Mutations

PSEN1 P433S

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685890 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a U.K. genetic screen of more than 3,000 samples of patients with dementia (Koriath et al., 2018). The carrier was a man diagnosed with AD with an unknown family history of dementia. Age at onset was 43 years. The mutation was absent from genetic variant databases, including ExAC, EVS, 1000G, and gnomAD.

The mutation was also reported in a Chinese family with seven members, spanning three generations, who experienced progressive memory decline starting in their 30s and subsequent psychotic symptoms (Shen et al., 2019). The proband's age at onset was 34 years. Memory loss was followed by  depression, agitation, and disorientation. In addition, language, attention, judgement, and problem-solving abilities deteriorated. Other affected family members included the proband's mother, maternal grandfather, two uncles, and two aunts. Like the proband, these individuals experienced memory loss in their 30s and followed a similar disease course. 

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

Neuropathology
Neuropathological data are unavailable, but the Chinese proband had hippocampal and cortical atrophy as revealed by MRI.

Biological Effect
Neuroblastoma cells expressing this mutation produced more Aβ42 and had an elevated Aβ42/Aβ40 ratio compared with cells expressing wildtype PSEN1 (Shen et al., 2019). Moreover, the mutation inhibited PSEN1 endoproteolysis, and enhanced Aβ43 production. The effects are consistent with the mutation causing a significant change in amino acid size and the site being on the edge of an intermembrane domain, next to several deleterious mutations.

Of note, P433 is part of the P433-A434-L435 (PAL) motif which has been implicated in APP binding to PSEN1 (Sato et al., 2008). In a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, the PAL motif appeared to facilitate the extension of APP residues 718 to 721, stabilizing and orienting the peptide bonds for cleavage (Zhou et al., 2019; Jan 2019 news). Deletion of the PAL motif crippled the proteolytic cleavage of the APP-C83 fragment.

Moreover, 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). Based on their proposed pathogenicity algorithm, Koriath and colleagues classified the mutation as likely deleterious (Koriath et al., 2018).

Last Updated: 12 Oct 2021

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References

News Citations

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

Paper Citations

  1. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  2. . Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization. Biochem Biophys Res Commun. 2019 Aug 13;516(1):264-269. Epub 2019 Jun 21 PubMed.
  3. . 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.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. . 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

Protein Diagram

Primary Papers

  1. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.

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