Mutations

PSEN1 G209E

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659429 G>A
dbSNP ID: rs63750053
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to GAA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation has been reported in two individuals. It was originally found in a patient with AD (Rogaeva et al., 2001), and subsequently reported in a Chinese man with early onset dementia (Xu et al., 2018). The latter experienced memory loss at age 43 with disorientation and an impaired ability to perform calculations. In subsequent years, his language fluency deteriorated and he presented with behavioral changes. At age 47, he suffered from apatheia, bradykinesia, and gatism, as well as increased limb muscle tone.

Neuropathology

Although neuropathological data are unavailable, brain MRI images of the Chinese mutation carrier showed global cerebral atrophy, particularly in the hippocampus. In addition, multiple subcortical white matter hyperintensities were observed in the temporal and parietal lobes, as well as adjacent to the lateral ventricles. FDG-PET revealed a global decrease in cerebral glucose metabolism, particularly affecting the temporal, parietal, and occipital lobes.

Biological Effect

Unknown. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in G209 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

Last Updated: 14 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. . The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
  3. . 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. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position

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