Mutations

PSEN1 S169del (ΔS169)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653586 TCA>---
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: TCA.TCT to ---.TCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This trinucleotide deletion mutation has been reported in a family from southern China (Guo et al., 2010). The pedigree contains four affected individuals in three generations. The clinical presentation in this family is fairly typical for AD. In contrast to the other reported mutations at the 169 codon, S169del does not appear to be associated with myoclonus, seizures, or pronounced personality changes. The proband developed progressive memory impairment at age 42, especially difficulties with short-term memory. Her mother developed similar symptoms at age 50 and died at age 60. A maternal aunt and uncle were also affected, with symptom onset at ages 42 and 45, the aunt dying at age 50 and the uncle alive at the time of the report (age 50). The mutation was detected in the two affected individuals tested as well as in two young family members (age 22 and 24) who were currently healthy, but suspected to be presymptomatic. The mutation was absent in three other unaffected family members and in 100 unrelated controls.

Neuropathology

Unknown; MRI of the proband showed generalized cerebral atrophy with enlargement of the ventricles and widening of the sulci (Guo et al., 2010).

Biological Effect

This is a trinucleotide deletion in a coding region which is predicted to result in the deletion of one amino acid (serine). In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, Aβ42 production was robustly decreased and Aβ40 production was undetectable (Sun et al., 2017). In contrast, the mutation was reported to leave Notch 1 cleavage and Notch signaling intact, both in vitro and in vivo (Zhang et al., 2018). However, cryo-electron microscopy studies indicate that, in wild-type PSEN1, serine 169 helps anchor the interface between PSEN1 and both APP and Notch fragments; its hydroxyl group forming H-bonds with carbonyl oxygen atoms in each of the two substrates (Zhou et al., 2019; Jan 2019 newsYang et al., 2019).

Last Updated: 02 Aug 2019

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References

News Citations

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

Paper Citations

  1. . A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer's disease. Neurosci Lett. 2010 Jan 1;468(1):34-7. Epub 2009 Oct 22 PubMed.
  2. . 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.
  3. . A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol Psychiatry. 2018 Jun 18; PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer's disease. Neurosci Lett. 2010 Jan 1;468(1):34-7. Epub 2009 Oct 22 PubMed.

Other mutations at this position

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