Mutations

PSEN1 V391F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683875 G>T
dbSNP ID: rs63751066
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was first identified in a French family with three affected members, spanning three generations, having probable or definite AD with onset between 42 and 45 years of age (Raux et al., 2005). The screen included 31 families in whom the coding regions of the PSEN1 and PSEN2 genes, as well as exons 16 and 17 of the APP gene, were sequenced from genomic DNA.

The mutation was subsequently found in two additional French families with AD diagnosed in seven and two members each, with ages of onset ranging between 54 and 55, and 45–50 (Wallon et al., 2012). In the family with seven affected members, the mutation was reported to co-segregate with disease.

Neuropathology
Unknown

Biological Effect
In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, production of Aβ40 was reduced and the Aβ42/Aβ40 ratio was elevated (Sun et al., 2017). Scores for in silico pathogenicity analysis can be found in the Alzheimer’s Disease & Frontotemporal Dementia Mutation Database.

Last Updated: 04 Apr 2019

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References

Paper Citations

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  2. . The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
  3. . 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.

External Citations

  1. Alzheimer’s Disease & Frontotemporal Dementia Mutation Database

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.

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