Mutations

PSEN1 L282R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinson's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664814 T>G
dbSNP ID: rs63750050
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Spanish woman affected by early onset Alzheimer’s disease (Aldudo et al., 1998). Clinical onset is considered to have occurred at age 49 and she died at age 54. Details related to her clinical symptoms were not reported. Her mother was affected at age 58, and two of her four siblings were affected, both at age 40. The average age of onset in the family was 43 ± 5 years. The average age of death for affected individuals in the family was 56 ± 3 years. Genetic analysis was only available for the proband, therefore segregation with disease could not be formally demonstrated.

This mutation was also identified in a second Spanish family (Gómez-Tortosa et al., 2010). The proband began to experience memory and concentration difficulties at the age of 35. By the age of 42 she had developed non-fluent aphasia, bilateral myoclonus, generalized seizures and a parkinsonian gait. She had a family history of dementia. Her father was affected by age 42 and died at age 49. Two of the proband’s paternal aunts were affected, at ages 48 and 50, with death at 54 and 58, respectively. Her paternal grandmother was similarly affected and had died at age 58. A brother of the proband was also a mutation carrier. He was clinically presymptomatic at age 37 with signs of hypometabolism in the parietotemporal areas by FDG-PET.

Also, a Chinese woman diagnosed with AD was identified in a large cohort study in South China in which 14 genes associated with neurodegenerative dementias from 1795 patients were sequenced (Jiao et al., 2021). Her age at onset was 52 years and her APOE genotype was APOE E3/E3. She had a family history of AD. Her symptoms included memory loss and language impairment.

Interestingly, another Chinese woman who also carried the mutation was initially diagnosed with Parkinson's disease (Sun et al., 2023). Her age at onset was 50 years and her symptoms included tremor, bradykinesia, rigidity, and postural instability. She also developed cognitive impairment, visual hallucinations, and compulsive behaviors. Stroke and epilepsy were recorded in her medical history. She had a family history of AD. 

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

Neuropathology

Autopsy of the first reported proband confirmed neuropathology consistent with the diagnosis of AD (Aldudo et al., 1998). An MRI scan of the Chiinese carrier with parkinsonian symptoms revealed a hemorrhagic lesion in the right occipital lobe (Sun et al., 2023).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates less Aβ42 than the wildtype protein, and undetectable amounts of Aβ40 (Sun et al., 2017). However, this assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Two subsequent, in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. In addition, both studies reported elevated Aβ43 levels. Of note, Liu and colleagues found no difference in the Aβ42/Aβ40 ratio between this variant and controls (Liu et al., 2022).

Although all three studies reported deleterious effects, there were some discrepancies. One of the cellular-based studies and the in vitro study found decreased production of Aβ40 and Aβ42 (Sun et al., 2017, Liu et all., 2022), but not the other cell-based study (Petit et al., 2022). 

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).

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. L282R: Experimental results vary somewhat, but all studies have revealed a damaging effect on APP processing.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. L282R: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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. . Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease. Neurosci Lett. 1998 Jan 16;240(3):174-6. PubMed.
  2. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
  3. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  4. . The genetic spectrum of a cohort of patients clinically diagnosed as Parkinson's disease in mainland China. NPJ Parkinsons Dis. 2023 May 17;9(1):76. PubMed.
  5. . 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.
  6. . 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.
  7. . 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.
  8. . Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  9. . Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. PubMed.
  10. . 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
  2. Sun et al., 2023

Further Reading

Papers

  1. . DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations. Hum Mutat. 1999;14(5):433-9. PubMed.
  2. . Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.

Protein Diagram

Primary Papers

  1. . Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease. Neurosci Lett. 1998 Jan 16;240(3):174-6. PubMed.

Other mutations at this position

Alzpedia

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