Mutations

PSEN2 T421M

Overview

Pathogenicity: Alzheimer's Disease : Benign
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227083195 C>T
dbSNP ID: rs756609078
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACG to ATG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13

Findings

This mutation was found in a screen of Japanese AD patients without a family history of disease and with age at onset under 60 years (Yagi et al., 2014). The proband’s symptoms, described as typical of AD, emerged at age 55.  Genotype information from the proband’s family was unavailable, so it is unclear whether the mutation was inherited or arose de novo. Of note, the proband was homozygous for the APOE4 allele.

The mutation was absent from 112 Japanese controls and from 147 patients with diseases other than AD. Although it was absent from the variant databases dbSNP137 and 1000 genomes in 2014, in 2021, seven heterozygotes, five of Asian ancestry, were reported in the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology
Unknown.

Biological Effect
In mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2, transfection of this variant resulted in decreased secretion of Aβ40 and Aβ42, with no effect on the Aβ42/Aβ40 ratio, compared with transfection of wildtype PSEN2 (Hsu et al., 2020).

In silico, the variant was predicted to be damaging by three function-prediction algorithms (SIFT, PolyPhen 2, and Pmut; Yagi et al., 2014), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, also suggesting a deleterious effect (CADD v.1.6, Nov 2021). Moreover, T421 is conserved in vertebrates, and one individual who had a deletion of its PSEN1 homolog, PSEN1 T440del, suffered from early onset parkinsonism and dementia (Ishikawa et al., 2005).

Last Updated: 12 Nov 2021

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References

Mutations Citations

  1. PSEN1 T440del

Paper Citations

  1. . Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 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.
  3. . A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 PubMed.

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