Mutations

PSEN1 I83T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637665 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, 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

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).

Last Updated: 09 Sep 2021

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References

Paper Citations

  1. . 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. . 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. . Refractory epilepsy in PSEN 1 mutation (I83T). Neurocase. 2020 Jun;26(3):167-170. Epub 2020 Apr 3 PubMed.
  4. . 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. . 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

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