Mutations

PSEN1 I83T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73170957 T>C
Position: (GRCh37/hg19):Chr14:73637665 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to ACC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in two Tunisian siblings affected by early onset Alzheimer’s disease (Achouri-Rassas et al., 2015). The reported pedigree shows 10 affected individuals over three generations. The siblings, a brother and sister, were diagnosed with AD at the ages of 55 and 64, respectively, meeting NINCDS-ADRDA criteria for probable AD. The siblings presented with prominent behavioral symptoms, along with depression, irritability, and visual hallucinations (Fray et al., 2015). Segregation with disease could not be assessed due to lack of DNA from family members. A subsequent publication reported refractory epilepsy emerging at age 4 in a 32-year-old carrier in the next generation of the same family (Fray et al., 2020). This patient had memory and attention deficits, as well as depression. Of note, except for this individual, epilepsy was not observed in any other family member.

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

Neuropathology

Unknown. In one case, MRI showed bilateral atrophy, especially in the parietal and temporal lobes (Fray et al., 2015). In the patient with epilepsy, brain MRI at the age of 31 showed cortical atrophy predominant in the frontal and temporal regions without obvious epileptogenic lesions (Fray et al., 2020).

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples.

In silico algorithms to predict the effects of this variant on protein function (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-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.

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: 01 Dec 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. Achouri-Rassas A, Ben Ali N, Fray S, Hadj Fredj S, Kechaou M, Zakraoui NO, Cherif A, Chabbi S, Anane N, Messaoud T, Gouider R, Belal S. Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset Alzheimer's disease. Neurobiol Aging. 2015 Oct;36(10):2904.e9-11. Epub 2015 Jun 12 PubMed.
  2. Fray S, Ali NB, Rassas AA, Kechaou M, Oudiaa N, Cherif A, Echebbi S, Messaoud T, Belal S. Early psychiatrics symptoms in familial Alzheimer's disease with presenilin 1 mutation (I83T). J Neural Transm (Vienna). 2016 Apr;123(4):451-3. Epub 2015 Dec 22 PubMed.
  3. Fray S, Rassas A, Messaoud T, Belal S. Refractory epilepsy in PSEN 1 mutation (I83T). Neurocase. 2020 Jun;26(3):167-170. Epub 2020 Apr 3 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. 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 variant database

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Achouri-Rassas A, Ben Ali N, Fray S, Hadj Fredj S, Kechaou M, Zakraoui NO, Cherif A, Chabbi S, Anane N, Messaoud T, Gouider R, Belal S. Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset Alzheimer's disease. Neurobiol Aging. 2015 Oct;36(10):2904.e9-11. Epub 2015 Jun 12 PubMed.

Other mutations at this position

View Table

Alzpedia

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