Mutations

PSEN1 S212Y

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659438 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCC to TAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a family with multiple affected family members. The proband was a Caucasian female with a history of memory problems beginning at age 38. She experienced progressive impairment and was diagnosed with dementia at the age of 44. At 55, she was still in a relatively mild stage of dementia, but activities of daily living were affected.

Her father had died at the age of 70 with a progressive dementia syndrome with onset around age 56. Details of his condition or prior family history were not known. Of the proband’s three siblings, two were affected. Onset in these siblings occurred at ages 41 and 44, with death of both reported at age 55. One of these siblings had autopsy-confirmed AD and was a mutation carrier. The genotype of the other affected sibling is not known. A 66-year-old sister was unaffected and did not carry the mutation. Therefore, segregation analysis suggests that the mutation segregates with disease in this family (Ringman et al., 2011).

A man who died with AD at age 55 in the U.S. was also reported to carry the mutation (Course et al., 2022). His APOE genotype was APOE2/E4. 

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

Neuropathology

Two carriers had autopsy-confirmed AD with neurofibrillary tangle pathology (Braak stage VI) and frequent neuritic plaques (Ringman et al., 2011; Course et al., 2022). In one case, severe amyloid angiopathy was noted in the cerebellum and occipital cortex, and α-synuclein pathology was detected in the amygdala (Ringman et al., 2011).

Biological Effect

A study that examined a range of Aβ peptides generated by this variant in human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this mutant revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. In an earlier study in which the variant was transfected into HEK293 cells expressing APP with the Swedish mutation, the mutant increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1 (Ringman et al., 2011).

An in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate also resulted in an elevated Aβ42/Aβ40 ratio, but the production of both peptides was dramatically reduced (Sun et al., 2017). 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).

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-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.

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. S212Y: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 14 Nov 2022

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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. . Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation. Neurosci Lett. 2011 Jan 10;487(3):287-92. Epub 2010 Nov 19 PubMed.
  2. . Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease. Brain. 2022 Aug 11; PubMed.
  3. . 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. . 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.
  5. . 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 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  6. . 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.

Other Citations

  1. Swedish mutation

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation. Neurosci Lett. 2011 Jan 10;487(3):287-92. Epub 2010 Nov 19 PubMed.

Alzpedia

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