Mutations

PSEN1 G209A

Overview

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

Findings

This mutation was found in a Korean woman with early onset Alzheimer’s disease (An et al., 2016). She presented with mild cognitive impairment and depression in her 40s. Her APOE genotype was E3/E3. Her mother had been diagnosed with an unspecified dementia, also in her 40s, and had died by age 60. The proband’s father and brother were unaffected. Segregation with disease could not be determined. One of the proband’s two daughters was a mutation carrier; she was asymptomatic in her 20s.

Neuropathology

Unknown. MRI showed global cortical atrophy, most prominent in the medial, temporal, and parietal lobes. FDG-PET revealed widespread bilateral hypometabolism, including in the temporal,  parietal, and frontal lobes.

Biological Effect

Unknown. In silico, this mutation was predicted likely damaging by PolyPhen2, SIFT, and Provean (Giau et al. 2019). 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. . Novel PSEN1 G209A mutation in early-onset Alzheimer dementia supported by structural prediction. BMC Neurol. 2016 May 20;16:71. PubMed.
  2. . Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. 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. . Novel PSEN1 G209A mutation in early-onset Alzheimer dementia supported by structural prediction. BMC Neurol. 2016 May 20;16:71. PubMed.

Other mutations at this position

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