Mutations

PSEN1 S169P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Myoclonic seizure, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653585 T>C
dbSNP ID: rs63750418
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCA to CCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was reported in a Spanish family with four affected members over two generations, a mother and three of her children (Ezquerra et al., 1999). The clinical phenotype in this family included myoclonus in addition to early onset dementia. The proband developed symptoms at the age of 31, starting with irritability, personality changes, and memory impairment.

Three of the proband’s offspring subsequently developed early onset AD, with a homogeneous age of onset (33, 34, and 35 years). Two of the siblings also had myoclonic jerks. Two affected individuals were genetically tested and found to carry the mutation, but segregation with disease could not be formally shown due to lack of available DNA from additional family members. The mutation was not detected in 100 controls from the general population or among 50 unrelated sporadic AD patients from Spain.

Neuropathology

Cerebral biopsy of the proband revealed numerous plaques and neurofibrillary tangles, neurite irregularities, neuronal lipofuscin, and mild astrocytosis, overall consistent with a diagnosis of Alzheimer’s disease (Ezquerra et al., 1999).

Biological Effect

In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, Aβ42 production was increased, whereas that of Aβ40 was decreased (Sun et al., 2017). 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: 01 Aug 2019

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References

News Citations

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

Paper Citations

  1. . A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures. Neurology. 1999 Feb;52(3):566-70. 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. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.

Further Reading

Papers

  1. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures. Neurology. 1999 Feb;52(3):566-70. PubMed.

Other mutations at this position

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