Mutations

PSEN2 T421M

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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 12

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. It was also absent from the variant databases dbSNP137 and 1000 genomes.

Neuropathology
Unknown.

Biological Effect
The biological effects of the mutation are unknown, but it was predicted to be pathogenic by three function-prediction algorithms (SIFT, PolyPhen 2, and Pmut). Moreover, T421 is conserved in vertebrates and deletion of its PSEN1 homolog, PSEN1 T440, correlated with early onset parkinsonism and dementia in one individual (Ishikawa et al., 2005).

Last Updated: 31 Oct 2019

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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. . 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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