Mutations

PSEN2 N141Y

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PM5, PP1, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885602 A>T
Position: (GRCh37/hg19):Chr1:227073303 A>T
dbSNP ID: rs61761208
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to TAC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a Han family from northern China. It is thought to be the first pathogenic PSEN2 mutation described in a Chinese family. The reported pedigree shows six affected members over three generations. The proband noticed forgetfulness at age 43 and died at age 55 with autopsy-confirmed Alzheimer's disease. Her grandfather, mother, and two aunts were also affected and died of dementia in their sixth decade. The proband's two brothers, who were developmentally delayed, died of cerebral hemorrhage in their 40s, reportedly without dementia. Segregation analysis supported pathogenicity; the N141Y mutation was detected in two affected family members and absent in five unaffected family members. It was also absent in 188 unrelated individuals (Niu et al., 2014).

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

Neuropathology

The proband had autopsy-confirmed AD with severe brain atrophy, especially of the parietal lobe, and numerous plaques and neurofibrillary tangles (Niu et al., 2014).

Biological Effect

As reported in a preprint, an experimental assay using human embryonic kidney cells revealed an elevation of the Aβ42/Aβ40 ratio (N141Y: 0.32 vs WT:0.15) and a decrease in the Aβ37/Aβ42 ratio (N141Y: 0.17 vs WT:0.44) (Liu et al., 2024). Notably, the latter ratio has been reported to outperform the former as an indicator of AD pathogenicity for PSEN1 variants (Liu et al., 2022, Apr 2022 news).

Also of note, N141Y’s homolog in PSEN1, N135Y, also increased the Aβ42/Aβ40 ratio (N135Y: 0.40 vs WT:0.15) and decreased the Aβ37/Aβ42 ratio (N135Y: 0.13 vs WT:0.41) (Liu et al., 2024 preprint). Across multiple PSEN1 and PSEN2 variants, the effects of PSEN1/PSEN2 homologs were correlated, and PSEN2 variants with known PSEN1 homologs were more likely to be classified as pathogenic than those without.

In silico analysis using SIFT, PolyPhen-2, and other programs predicted a damaging and/or probably damaging effect (Niu et al., 2014) and the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 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.

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.

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. N141Y: 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: 15 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?

Paper Citations

  1. Niu F, Yu S, Zhang Z, Yi X, Ye L, Tang W, Qiu C, Wen H, Sun Y, Gao J, Guo Y. A novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer's disease in a Chinese Han family. Neurobiol Aging. 2014 Oct;35(10):2420.e1-5. Epub 2014 Apr 18 PubMed.
  2. Liu L, Schultz S, Saba A, Yang H-S, Li A, Selkoe D, Chhatwal J. The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1. 2024 Jun 28 10.1101/2024.06.22.600217 (version 1) bioRxiv.
  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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Niu F, Yu S, Zhang Z, Yi X, Ye L, Tang W, Qiu C, Wen H, Sun Y, Gao J, Guo Y. A novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer's disease in a Chinese Han family. Neurobiol Aging. 2014 Oct;35(10):2420.e1-5. Epub 2014 Apr 18 PubMed.

Other mutations at this position

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Alzpedia

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