Mutations

PSEN2 P123L

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073250 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to CTA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a Chinese family affected by familial Alzheimer’s disease (Xia et al., 2015). The reported pedigree shows four affected individuals over four generations. In this family the disease presented as cognitive decline with parkinsonism and myoclonic jerks. The proband developed symptoms at age 57, staring with memory loss and personality changes, including irritability and apathy. She later developed rigidity in her hands and a persistent myoclonic jerking of her left hand. 

Of the 15 family members genotyped, seven were mutation carriers; however, only the proband met diagnostic criteria for AD. The other six mutation carriers were asymptomatic at the time of the report at ages 81, 58, 49, 53, 37, and 27 years. The mutation was absent from nine unaffected family members, 100 controls, and the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

Unknown. Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions.

Biological Effect

In a mouse neuroblastoma cell assay, this variant increased Aβ42 and decreased Aβ40 secretion, resulting in an approximately twofold increase in the Aβ42/Aβ40 ratio compared with that of cells expressing wildtype PSEN2 (Hsu et al., 2020).

This mutation was predicted to be probably damaging by in silico analysis (Xia et al., 2015, Hsu et al., 2020) and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Last Updated: 02 Nov 2021

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References

Paper Citations

  1. . Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. Neurobiol Aging. 2015 Dec;36(12):3334.e13-8. Epub 2015 Sep 8 PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. Neurobiol Aging. 2015 Dec;36(12):3334.e13-8. Epub 2015 Sep 8 PubMed.

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