Mutations

PSEN2 N43N

Overview

Pathogenicity: Alzheimer's Disease : Benign
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227069737 C>T
dbSNP ID: rs6759
Coding/Non-Coding: Coding
Mutation Type: Point, Silent
Codon Change: AAC to AAT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 4

Findings

This synonymous variant is very common worldwide, observed in roughly 50 percent of individuals in the gnomAD variant database (v2.1.1, Oct 2021), and at a similar frequency in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death (Oct 2021). Current evidence indicates it is a benign polymorphism.

One study described its presence, in heterozygous form, in four Turkish patients diagnosed with early onset Alzheimer’s disease (AD) together with another, very common synonymous variant, PSEN2 A23A (Eryilmaz et al., 2021). One of these carriers also had the PSEN1 mutation L364P. Age at onset ranged from 55 to 61 years of age. The N34N/A23A variant combination was also detected in a family with early onset AD. In this case, all members were A23A homozygotes with a mix of N34N homo- and heterozygotes. Several unaffected carriers were identified in this family, as well as in family members of one of the patients. Their ages were not reported.

Neuropathology
Neuropathological data are unavailable. Three of four carriers of the N43N/A23A variants were reported to have atrophy assessed by MRI that was consistent with AD (Eryilmaz et al., 2021). The fourth carrier had no detectable AD-relevant atrophy at age 55.

Biological Effect
The biological effect of this variant is unknown but, as expected, its PHRED-scaled CADD score, which integrates diverse information in silico, was very low (0.635), strongly suggesting it does not have a damaging effect (CADD v.1.6, Oct 2021). Nonetheless, Eryilmaz and colleagues hypothesized that together with A23A, it may contribute to early onset AD. Other possibilities include the presence of pathogenic mutations in other genes or regions beyond the coding regions and exon-intron boundaries of PSEN1, PSEN2, APP, and TREM2 which were screened in the study (Eryilmaz et al., 2021).

Last Updated: 30 Oct 2021

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References

Mutations Citations

  1. PSEN2 A23A

Paper Citations

  1. . Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.

Other Citations

  1. HEX

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Evaluation of the Clinical Features Accompanied by the Gene Mutations: The 2 Novel PSEN1 Variants in a Turkish Early-onset Alzheimer Disease Cohort. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):214-222. PubMed.

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