Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186879_73186881 ATC>---
Position: (GRCh37/hg19):Chr14:73653587_73653589 ATC>---
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: 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. It was also absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

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 variant is a trinucleotide deletion which includes the last nucleotide of the serine 169 codon and the first two nucleotides of the serine 170 codon. The consequence is loss of one serine which can be mapped to either S169 or S170, and hence, the mutation has been referred to as S169del or S170del. Most publications refer to it as S169del, but according to the Human Genome Variation Society, it should be named S170del.

Experiments in transfected cells revealed the mutant increased the Aβ42/40 ratio and decreased the Aβ37/40 ratio, both being predictive of pathogenicity, with the latter outperforming the former in its ability to distinguish between AD and control samples (Liu et al., 2022, Apr 2022 news). An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate also showed an increased Aβ42/40 ratio (Sun et al., 2017). Of note, while the cell-based experiments found increased production of Aβ42 and Aβ40 (Liu et al., 2022), the in vitro study showed a reduction of both (Sun et al., 2017). This may be due to deficient cleavage efficiency in this assay—68 of the 138 mutant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Cryo-electron microscopy studies indicate that, in wild-type PSEN1, S169 helps anchor the interface between PSEN1and APP with its hydroxyl group forming H-bonds with the substrate (Zhou et al., 2019; Jan 2019 news; 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). Of note, although S169del was reported to leave Notch 1 cleavage and Notch signaling intact both in vitro and in vivo (Zhang et al., 2018), a cryo-EM study suggests S169 interacts with Notch as it does with APP (Yang et al., 2019).

In silico algorithms to predict the effects of this variant on protein function yielded conflicting results (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. S169del: 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.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. S169del: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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

Paper Citations

Guo J, Wei J, Liao S, Wang L, Jiang H, Tang B. 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.
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.
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.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
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.
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.
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.
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.
Zhang S, Cai F, Wu Y, Bozorgmehr T, Wang Z, Zhang S, Huang D, Guo J, Shen L, Rankin C, Tang B, Song W. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol Psychiatry. 2018 Jun 18; PubMed.
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.
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.

Mutations

PSEN1 S169del (S170del)

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