Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219182 C>T
Position: (GRCh37/hg19):Chr14:73685890 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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).

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-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. P433S: Variant located at edge of mutational hot spot; 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.

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

Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. 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.
Shen L, Qin W, Wu L, Zhou A, Tang Y, Wang Q, Jia L, Jia J. 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.
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.
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 P433S

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