Mutations

PSEN1 F386S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683861 T>C
dbSNP ID: rs63749860
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTC to TCC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was found in a family with five affected members, spanning three generations, having probable or definite AD with onset between 37 and 58 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.

Neuropathology
Unknown

Biological Effect

  1. In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, production of Aβ40, and to a lesser extent Aβ42, was reduced (Sun et al., 2017). However, in HEK 239 transfected cells, the mutant was reported to increase Aβ40 and Aβ42 secretion (Dumanchin et al., 2016). In both cases, the Aβ42/Aβ40 ratio was elevated. Scores for in silico pathogenicity analysis can be found in the Alzheimer’s Disease & Frontotemporal Dementia Mutation Database

Last Updated: 05 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. . 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.
  3. . Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.

External Citations

  1. Alzheimer’s Disease & Frontotemporal Dementia Mutation Database

Further Reading

Papers

  1. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.

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.

Other mutations at this position

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