Mutations

PSEN1 F388L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683868 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTC to TTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

The F388L mutation was found in a Chinese family with a strong history of dementia (Zhan et al., 2016). The family consisted of five siblings, three of whom had a history of cognitive impairments, as did the father. The proband was diagnosed with AD according to the NINCDS-ADRDA criteria for possible or probable AD. The proband’s symptoms began with progressive memory impairment. Subsequently she developed psychosis, paranoid delusions, and impairments in verbal expression and visuospatial tasks. The average age of onset in the family was 43 years (range 42-45). The father and one sibling both died three years after onset (at ages 45 and 48, respectively). The two surviving affected siblings were carriers of the F388L mutation while the unaffected siblings were not carriers, demonstrating that the mutation segregates with disease. Other mutations in APP, PSEN1, and PSEN2 known to be associated with familial AD were not found in this family. Additionally, the proband was homozygous for APOE3 and did not have any TREM2 mutations associated with AD risk. The F388L mutation was absent from 360 healthy Chinese control subjects.

Neuropathology

Unknown.

Biological Effect

In a cell line stably expressing the APP751 isoform, expression of presenilin-1 with the F388L mutation increased the amount of Aβ42 and the Aβ42/Aβ40 ratio relative to cells expressing wildtype presenilin-1 (Zhan et al., 2016).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that F388 helps form a shallow hydrophobic pocket for part of the C-terminal portion of the APP transmembrane helix (Zhou et al., 2019; Jan 2019 news). 

Last Updated: 10 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . A novel presenilin 1 mutation (F388L) identified in a Chinese family with early-onset Alzheimer's disease. Neurobiol Aging. 2017 Feb;50:168.e1-168.e4. Epub 2016 Oct 15 PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 mutation (F388L) identified in a Chinese family with early-onset Alzheimer's disease. Neurobiol Aging. 2017 Feb;50:168.e1-168.e4. Epub 2016 Oct 15 PubMed.

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