Mutations

PSEN1 G417A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Reference Assembly: GRCh37 (105)
Position: Chr14:73685843 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to GCT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a Korean man presenting with symptoms of AD and parkinsonism (Giau et al., 2018). Memory impairment started at age 34 and advanced rapidly with progressive language disturbance, visuo-spatial dysfunction, and behavioral changes. The patient also had a stooped posture, rigidity, and bradykinesia. None of his family members had reported similar symptoms. The mutation was absent from 662 unaffected individuals in the Korean Reference Genome Database, as well as from the ExAC and 1000 Genomes databases.

Neuropathology
Neuropathological data are unavailable, but MRI and PET scans were consistent with AD pathology. MRI revealed bilateral atrophy of parietal and anterior temporal regions, with diffuse cortical atrophy, and FDG-PET showed hypometabolism in the entire cortex, particularly in parietal areas. Moreover, a PiB-PET scan revealed widespread diffuse amyloid deposition, including the cerebellum, and the frontal, parietal, and temporal cortices.

Biological Effect
The biological effect of this mutation is unknown, but it is in a conserved site and in silico analysis tools, including PolyPhen2, SIFT, and Provean, predict it is damaging. Moreover, ExPASy algorithms indicated significant changes in bulkiness, polarity, and hydrophobicity. The authors noted this may result in reduced flexibility within the helix of transmembrane domain-VIII, a hypothesis supported by 3D structural modeling. Additionally, the mutation may impair splicing, as it is near a known acceptor and a potential donor splice sites.

Last Updated: 03 Jul 2019

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References

Paper Citations

  1. . Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. Neurobiol Aging. 2018 Dec;72:188.e13-188.e17. Epub 2018 Aug 9 PubMed.

Further Reading

Papers

  1. . Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.

Protein Diagram

Primary Papers

  1. . Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. Neurobiol Aging. 2018 Dec;72:188.e13-188.e17. Epub 2018 Aug 9 PubMed.

Other mutations at this position

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