Mutations

PSEN1 V272D

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73664784 T>A
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to GAT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in an Iraqi man with a family history of early onset dementia (Mengel et al., 2019). Nine family members of the proband’s family, spanning three generations, developed cognitive deterioration between age 40 and 45, leading to death at 45 to 52 years. At age 46, the proband presented with language impairments, having lost his ability to communicate in his second language a few months earlier, and having trouble finding words in his native tongue, as well as expressing phonematic and semantic paraphrasia. He was also disoriented in time and space, and suffered from short-term memory loss. At age 51, the proband was unable to speak or follow simple instructions and was mostly bedridden.
Based on the evolution of cognitive symptoms and the mutation type, the authors provided a tentative diagnosis of a logopenic variant of AD.

Neuropathology
Neuropathological data are unavailable, but MRI revealed frontotemporal atrophy, with a generalized reduction in brain volume and minor atrophy of the temporal lobe and hippocampus. AD biomarkers in cerebrospinal fluid, including Aβ42, Aβ40, tau and phosphorylated tau, were in the normal range.

Biological Effect
When overexpressed in PSEN1/2 double knockout HEK293 cells, the mutant increased the ratio of Aβ42/Aβ40 in the culture medium, but not to the extent that a previously reported mutant at the same position, V272A, did. The V272 position is conserved between PSEN1 and PSEN2, but is not in a transmembrane domain (Jimenez-Escrig et al., 2004).

Last Updated: 20 Sep 2019

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References

Mutations Citations

  1. PSEN1 V272A

Paper Citations

  1. . A novel V272D presenilin mutation associated with logopenia, disorientation, and apraxia in an autosomal-dominant Alzheimer's disease family. Neurobiol Aging. 2019 Aug 7; PubMed.
  2. . New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism. Eur J Neurol. 2004 Oct;11(10):663-9. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel V272D presenilin mutation associated with logopenia, disorientation, and apraxia in an autosomal-dominant Alzheimer's disease family. Neurobiol Aging. 2019 Aug 7; PubMed.

Other mutations at this position

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