Mutations

PSEN1 V96F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637703 G>T
dbSNP ID: rs63750601
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to TTC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was first identified in a Japanese family. The reported pedigree consisted of four affected family members over three generations. All affected individuals had early onset Alzheimer’s disease, with a mean age at onset of 52.5 ± 5.07 years (range: 49 to 60 years). The mutation was not found in unaffected family members or in 100 control individuals (Kamino et al., 1996). 

The mutation was also found in two siblings from Malaysia with early onset AD (Giau et al., 2019). Both individuals had symptoms that began at age 40. In addition to memory loss, the patients experienced apathy and withdrawal. Both patients had an APOE3/APOE4 genotype.

Neuropathology

Unknown.

Biological Effect

In vitro studies revealed a robust decrease in Aβ42 and Aβ40 production, as well as drastically reduced autoproteolytic endopeptidase activity (Brunkan et al., 2005; Sun et al., 2017). In cultured COS-1 cells, the Aβ42/Aβ40 ratio was increased two-fold (Kamino et al., 1996). In silico analyses predicted this mutation to be damaging using the PolyPhen algorithm, but tolerated, according to the SIFT algorithm (Giau et al., 2019). 

Last Updated: 29 Oct 2019

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References

Paper Citations

  1. . Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.
  2. . APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int J Mol Sci. 2019 Sep 25;20(19) PubMed.
  3. . Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and gamma-secretase activity. J Neurochem. 2005 Sep;94(5):1315-28. PubMed.
  4. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neurosci Lett. 1996 Apr 26;208(3):195-8. PubMed.

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