Mutations

PSEN1 F177S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653610 T>C
dbSNP ID: rs63749806
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTT to TCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001).

Subsequently, the mutation was reported in two members of a German family spanning seven generations with eight of 12 members affected by AD (Hausner et al., 2014).  Onset of dementia was between 29 and 31 years of age, with death before age 40. The dementia progressed rapidly and neurological features, including myoclonia, epileptic seizures, and pyramidal signs, were reported. There was little variability between individuals’ disease progression.

The mutation was also found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband suffered from memory loss when he was 30 years old, and developed involuntary movements, cerebellar ataxia, and difficulties speaking and swallowing. Three members of his family, spanning two generations, were affected by dementia, two of whom died in their 30s. 

 
Neuropathology
Autopsies of two members of the German family who were not tested genetically revealed neuropathology typical of AD, with cortical brain atrophy, abundant senile plaques, and neurofibrillary tangles (Hausner et al., 2014). In addition, in two affected mutation carriers, MRI revealed cortical atrophy which was particularly pronounced in the temporal regions and hippocampus. In one of these cases, frontal regions and the cerebellum were markedly affected as well (Jiang et al., 2019). Moreover, FDG-PET scans of two affected mutation carriers showed a progressive drop in parietal and temporoparietal glucose metabolism (Hausner et al., 2014). Levels of Aβ42 were decreased, while total tau was increased in the CSF of one of these patients.

Biological Effect
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).

Last Updated: 13 Aug 2019

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References

News Citations

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

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Clinical characterization of a presenilin 1 mutation (F177S) in a family with very early-onset Alzheimer's disease in the third decade of life. Alzheimers Dement. 2013 Jul 11; PubMed.
  3. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. . Structural basis of Notch recognition by human γ-secretase. Nature. 2019 Jan;565(7738):192-197. Epub 2018 Dec 31 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

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