Mutations

PSEN1 L282F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198105 C>T
Position: (GRCh37/hg19):Chr14:73664813 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Japanese woman diagnosed with probable Alzheimer’s disease based on NINCDS-ADRDA criteria (Hamaguchi et al., 2009). She started to develop memory impairment at age 53. She had a family history of dementia, but genetic analysis was performed only on the proband. Her sister was diagnosed with dementia at the age of 49. The proband's mother died at the age of 80 without dementia. Two of the mother’s five siblings developed dementia, one in her 60s and one in her 50s. The proband’s father had died young without dementia. Information is not available about the paternal line, therefore it remains unclear if the mutation was transmitted through the maternal line with incomplete penetrance observed in the proband’s mother. A subsequent study described a Japanese man carrying the mutation with AD onset at 54 years of age (Islam et al., 2022).

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

Neuropathology

Unknown. MRI of the proband showed mild medial temporal atrophy. FDG-PET showed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri (Hamaguchi et al., 2009).

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed decreased Aβ37/Aβ42, an indicator of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). However, the Aβ42/Aβ40 ratio was similar to controls. Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. Increased levels of Aβ43 were also observed.

Interestingly, a study of the PSEN inhibitor MRK-560 which inhibits the activity of PSEN1, but not PSEN2, identified L282 as one of two amino acids responsible for MRK-560's isoform-dependent sensitivity (Guo et al., 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).

Research models

An induced pluripotent stem cell line has been generated from skin fibroblasts of a patient carrying this mutation (Poon et al., 2016).

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. L282F: Although experimental data were mixed, the preponderance of evidence indicated a damaging effect.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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: 18 May 2023

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. Hamaguchi T, Morinaga A, Tsukie T, Kuwano R, Yamada M. A novel presenilin 1 mutation (L282F) in familial Alzheimer's disease. J Neurol. 2009 Sep;256(9):1575-7. PubMed.
  2. Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 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. Guo X, Wang Y, Zhou J, Jin C, Wang J, Jia B, Jing D, Yan C, Lei J, Zhou R, Shi Y. Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. PubMed.
  5. 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.
  6. Poon A, Li T, Pires C, Nielsen TT, Nielsen JE, Holst B, Dinnyes A, Hyttel P, Freude KK. Derivation of induced pluripotent stem cells from a familial Alzheimer's disease patient carrying the L282F mutation in presenilin 1. Stem Cell Res. 2016 Nov;17(3):470-473. Epub 2016 Sep 28 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

Papers

  1. Poon A, Li T, Pires C, Nielsen TT, Nielsen JE, Holst B, Dinnyes A, Hyttel P, Freude KK. Derivation of induced pluripotent stem cells from a familial Alzheimer's disease patient carrying the L282F mutation in presenilin 1. Stem Cell Res. 2016 Nov;17(3):470-473. Epub 2016 Sep 28 PubMed.

Protein Diagram

Primary Papers

  1. Hamaguchi T, Morinaga A, Tsukie T, Kuwano R, Yamada M. A novel presenilin 1 mutation (L282F) in familial Alzheimer's disease. J Neurol. 2009 Sep;256(9):1575-7. PubMed.

Other mutations at this position

View Table

Alzpedia

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