Mutations

PSEN2 D439A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.13642A>C
Genomic Mutation Name (NT1): g.29977A>C
dbSNP ID: rs63750110
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: GAC to GCC

Findings

This mutation was identified in a three-generation Spanish kindred from Barcelona, known as "Barc1". The proband developed behavioral disturbances and progressive cognitive decline starting at age 52. He had a diagnosis of probable AD. The proband's mother had AD (age of onset: 60 years). The proband's father had dementia (age of onset: 67 years). The mutation was absent in the proband's six cognitively healthy relatives. It was also absent in 130 unrelated individuals who were also screened (50 healthy control subjects and 80 patients with AD) indicating that it is not likely to be a common polymorphism (Lleó et al., 2001; Lleó et al., 2002).

Neuropathology

The proband had moderate cortical atrophy in the frontal and parietal regions (Lleó et al., 2001).

Biological Effect

This residue is located at the C-terminal end of the PSEN2 protein. It is conserved in PSEN1. When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the D439A variant did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared to wild-type PSEN2. When cotransfected with APP carrying the Swedish mutation, PSEN2 with the D439A variant did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005).

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References

Paper Citations

  1. . A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease. Neurology. 2001 Nov 27;57(10):1926-8. PubMed.
  2. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.
  3. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease. Neurology. 2001 Nov 27;57(10):1926-8. PubMed.