Mutations

PSEN1 S365A

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73678614 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCC to GCC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon10

Findings

This variant was found in  a woman who presented with AD symptoms at age 55, and was not present in her two healthy siblings (Clarimón et al., 2008, Guerreiro et al., 2010). Although the proband’s father suffered from dementia, his age of onset was 70. 

Neuropathology

Unknown.

Biological effect

In one study, in vitro production of Aβ38, Aβ40, Aβ42, and Aβ43, as well as the Aβ42/Aβ40 ratio, were found to be similar to those of wild-type PSEN1 (Matz 2015). A subsequent in vitro study found production of Aβ40 and Aβ42 moderately increased, with no change in the Aβ42/Aβ40 ratio (Sun et al., 2017). However, the phosphorylation status of this site appears to modulate a PSEN1 calcium-triggered conformational change linked to increased Aβ42/Aβ40 (Maesako et al., 2017).

The residue is not conserved between PSEN1 and PSEN2 and is not in a transmembrane domain. It was originally classified as possibly pathogenic (Guerreiro et al., 2010). In a subsequent study it was described as most likely having reduced penetrance, given its allele count of five and frequency of 0.0020 percent in the gnomAD variant database (Koriath et al., 2018).

 

Last Updated: 25 Jul 2019

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References

Paper Citations

  1. . Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  3. . Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production. J Neurochem. 2015 May;133(3):409-21. Epub 2015 Feb 24 PubMed.
  4. . 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.
  5. . Pathogenic PS1 phosphorylation at Ser367. Elife. 2017 Jan 30;6 PubMed.
  6. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Other mutations at this position

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