Mutations

PSEN1 S169L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186878 C>T
Position: (GRCh37/hg19):Chr14:73653586 C>T
dbSNP ID: rs63751210
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCA to TTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first reported in a patient known as Perth-4, who developed progressive forgetfulness, clumsiness and speech difficulty at the age of 31 (Taddei et al., 1998). She later developed myoclonus and seizures. Her condition progressed to end-stage dementia over several years and she died at the age of 37. Her mother and sister died with dementia at 36 and 42 years old, respectively. The proband had a brother apparently unaffected at the age of 45. Segregation could not be formally assessed, but the pattern of inheritance suggests autosomal-dominant transmission in this family.

A second family, known as family G, has been described carrying this mutation; two affected family members experienced early onset myoclonus, seizures, and dementia. An extensive pedigree was constructed with 73 members over five generations; only the proband and his mother were affected. The proband’s maternal grandparents, who were originally from Eastern Europe, lived beyond the age of 80 and were not reported to have suffered from any neurological disorder. The proband began to experience memory loss, periods of confusion, and disorientation at age 29. Family members noticed bizarre behaviors and personality changes at age 30. He developed arm twitching and seizures and died at the age of 40. His mother also experienced symptom onset, notably forgetfulness and personality changes, at age 29. Seizures developed within one year. At age 33, a neurological examination found myoclonus, dysarthria, hyperreflexia, intention tremor, and gait ataxia. She died at age 38 with a diagnosis of progressive myoclonus epilepsy, Unverricht-Lundborg type. The proband was the only member of the family to be tested genetically, therefore segregation with disease could not be assessed (Takao et al., 2001).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, June 2021).

Neuropathology

A brain biopsy of one affected mutation carrier at the age of 33 showed abundant neurofibrillary tangles, diffuse and compact plaques, and neuritic changes. Four years later, an autopsy confirmed the presence of typical AD pathology, finding extensive plaques and tangles in the cortex and hippocampus. Marked cortical atrophy was observed, as well as depigmentation of the substantia nigra, but no Lewy bodies. Extensive neuronal loss was noted in the cortex as well as the cerebellum (Taddei et al., 1998).

A detailed neuropathological assessment is also available for an unrelated individual with this mutation, the proband from family G. Not surprisingly, he had severe brain atrophy and characteristic histopathologic lesions of AD, including severe deposition of Aβ in the cortex. Unusual features included diffuse Aβ deposits in the cerebellar cortices and subcortical white matter as well as numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes. The origin of the ectopic neurons is unknown, but they have been attributed to errant migration during brain development (Takao et al., 2001).

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). Moreover, a subsequent study in transfected mutant cells showed the Aβ (37 + 38 + 40) / (42 + 43) ratio to be only 13.92 percent that of control cells expressing wildtype PSEN1 (Schultz et al., 2024; Aug 2024 conference news).  This ratio, originally proposed by Chávez-Gutiérrez and colleagues (Petit et al., 2022) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Cryo-electron microscopy studies indicate that, in wild-type PSEN1, S169 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. S169L: 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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 27 Aug 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. How Presenilin Mutations Hobble γ-Secretase Predicts Onset, Progression
  3. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  4. Caught in the Act: Cryo-EM Exposes γ-Secretase Catalytic Pose

Paper Citations

  1. Taddei K, Kwok JB, Kril JJ, Halliday GM, Creasey H, Hallupp M, Fisher C, Brooks WS, Chung C, Andrews C, Masters CL, Schofield PR, Martins RN. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.
  2. Takao M, Ghetti B, Murrell JR, Unverzagt FW, Giaccone G, Tagliavini F, Bugiani O, Piccardo P, Hulette CM, Crain BJ, Farlow MR, Heyman A. Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures. J Neuropathol Exp Neurol. 2001 Dec;60(12):1137-52. PubMed.
  3. 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.
  4. Schultz SA, Liu L, Schultz AP, Fitzpatrick CD, Levin R, Bellier JP, Shirzadi Z, Joseph-Mathurin N, Chen CD, Benzinger TL, Day GS, Farlow MR, Gordon BA, Hassenstab JJ, Jack CR Jr, Jucker M, Karch CM, Lee JH, Levin J, Perrin RJ, Schofield PR, Xiong C, Johnson KA, McDade E, Bateman RJ, Sperling RA, Selkoe DJ, Chhatwal JP, Dominantly Inherited Alzheimer Network. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 2024 Sep;23(9):913-924. Epub 2024 Jul 26 PubMed.
  5. Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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. Miravalle L, Murrell JR, Takao M, Glazier B, Piccardo P, Vidal R, Ghetti B. Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002 Jul-Aug; 23(S1):322.

Protein Diagram

Primary Papers

  1. Taddei K, Kwok JB, Kril JJ, Halliday GM, Creasey H, Hallupp M, Fisher C, Brooks WS, Chung C, Andrews C, Masters CL, Schofield PR, Martins RN. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PubMed.

Other mutations at this position

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Alzpedia

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