Mutations

PSEN1 S169P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonic seizure
Position: (GRCh38/hg38):Chr14:73186877 T>C
Position: (GRCh37/hg19):Chr14:73653585 T>C
dbSNP ID: rs63750418
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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. It was also absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

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

Experiments in transfected cells revealed the mutant increased the Aβ42/40 ratio and decreased the Aβ37/40 ratio, both being predictive of AD, with the latter outperforming the former (Liu et al., 2022, Apr 2022 news). An in vitro assay using purified proteins also found an increase in the Aβ42/40 ratio (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 news; Yang et al., 2019; Odorčić et al., 2024; Guo et al., 2024; Jun 2024 news). Moreover, molecular dynamics simulations have implicated S169 in the formation of an internal docking site that stabilizes substrate binding (Chen and Zacharias, 2022).

Several in silico algorithms (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-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. S169P: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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: 11 Jun 2024

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. Caught in the Act: Cryo-EM Exposes γ-Secretase Catalytic Pose

Paper Citations

  1. Ezquerra M, Carnero C, Blesa R, Gelpí JL, Ballesta F, Oliva R. A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures. Neurology. 1999 Feb;52(3):566-70. PubMed.
  2. 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.
  3. Sun L, Zhou R, Yang G, Shi Y. 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.
  4. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
  6. Odorčić I, Hamed MB, Lismont S, Chávez-Gutiérrez L, Efremov RG. Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform. Nat Commun. 2024 May 27;15(1):4479. PubMed.
  7. Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 PubMed.
  8. Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.
  9. 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 v2.1.1

Further Reading

Papers

  1. Lleó A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Peña-Casanova J, Rojo A, Oliva R. 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.

Protein Diagram

Primary Papers

  1. Ezquerra M, Carnero C, Blesa R, Gelpí JL, Ballesta F, Oliva R. 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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Alzpedia

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