Mutations

PSEN1 F177V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653609 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTT to GTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first identified in a screen of 148 Chinese individuals diagnosed with familial Alzheimer’s disease (Gao et al., 2019). The search focused on the APP, PSEN1, and PSEN2 genes, including exons 3-12 of PSEN1. The carrier of F177V was a woman with age at onset of 45 years. At 50, her symptoms included memory impairment, executive dysfunction, disorientation, dyscalculia, and disrupted visuospatial skills. Her APOE genotype was E3/E4.

A subsequent study reported co-segregation of the mutation with AD in a Chinese family spanning three generations with a mean age at onset of 39 years (Jiang et al., 2020). The mutation was present in five family members and absent from three healthy members, as well as from the gnomAD variant database. Two affected siblings presented with memory deficits as their first symptom and one of them went on to develop neuropsychiatric symptoms, including depression and anxiety. Another three affected members initially presented with anxiety and/or behavioral changes. One of these individuals gradually developed memory deficits, but the other two showed no signs of memory impairment one to two years later.

Neuropathology
Neuropathological data are unavailable, but an MRI scan of one patient revealed global brain atrophy, especially in the temporal region and hippocampus (Jiang et al., 2020).

Biological Effect
In cell transfection studies using neuroblastoma cells over-expressing APP751, the mutant protein increased both the production of Aβ42 and the ratio of Aβ42 over Aβ40, as compared with wild-type PSEN1 (Jiang et al., 2020).

The substitution of a phenylalanine with a valine is expected to decrease interactions with other hydrophobic residues, possibly affecting protein structure (Gao et al., 2019). Cryo-electron microscopy studies of the atomic structure of γ-secretase bound to Notch or APP fragments indicate F177 directly interacts with residues from Notch, but not APP (Zhou et al., 2019; Yang et al., 2019; Jan 2019 news). Two other mutations at this site, F177L and F177S, have been reported in individuals with a strong family history of AD. In silico analyses, including PolyPhen, SIFT, MutationTaster, and CADD (28.3), predicted the mutation is damaging (Gao et al., 2019Jiang et al., 2020). Also, orthologous sequence alignments revealed F177 is an evolutionarily conserved residue.

The mutation was first classified as probably pathogenic (Gao et al., 2019) and subsequently as pathogenic (Jiang et al., 2020) based on ACMG standards (Richards et al., 2015).

Last Updated: 14 Aug 2020

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References

News Citations

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

Mutations Citations

  1. PSEN1 F177L
  2. PSEN1 F177S

Paper Citations

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
  2. . A Pathogenic Variant p.Phe177Val in PSEN1 Causes Early-Onset Alzheimer's Disease in a Chinese Family. Front Genet. 2020;11:713. Epub 2020 Jul 10 PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.
  5. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.

Other mutations at this position

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