Mutations

PSEN1 G217D

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Parkinsonism, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659453 G>A
dbSNP ID: rs63750444
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to GAT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a family of Japanese origin with five individuals, spanning two generations, afflicted by early onset dementia and motor impairments (Takao et al., 2002). Two siblings had dementia and parkinsonism with impaired gait, stooped posture, rigidity, and bradykinesia. The proband was 42 years old and his sister in her late 30s at age of onset. Only the sister was genotyped and found to be a carrier of the mutation. The variant was absent from 30 Caucasians and 30 unrelated Japanese controls.

Neuropathology
In both cases examined, neuropathology included numerous cotton wool plaques, neuritic plaques, severe amyloid angiopathy, neurofibrillary tangles, neuronal loss, and gliosis. Cotton wool plaques, Aβ42-positive and containing mostly neuropil elements and extracellular amyloid fibrils, were found in the cortex, caudate nucleus, putamen, claustrum, thalamus, substantia innominate, and colliculi. The authors hypothesize that the abundance of these plaques in the striatum may underlie the parkinsonian syndrome observed in the patients.

MRI and CT scans of the proband’s sister’s brain showed severe atrophy of the frontal and temporal regions and mild atrophy of the cerebellum. In this same patient, SPECT revealed hypoperfusion of the frontal, temporal, and parietal regions.

Biological Effect
Unknown.

Research Models

Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50 year-old AD patient (Auboyer et al., 2019).

Last Updated: 23 Aug 2019

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References

Paper Citations

  1. . Generation of induced pluripotent stem cells (IRMBi001-A) from an Alzheimer's disease patient carrying a G217D mutation in the PSEN1 gene. Stem Cell Res. 2019 Jan;34:101381. Epub 2019 Jan 3 PubMed.
  2. . A novel mutation (G217D) in the Presenilin 1 gene ( PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol. 2002 Aug;104(2):155-70. PubMed.

Further Reading

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002 Jul-Aug; 23(S1):322.
  2. . A novel mutation (G217D) in the Presenilin 1 gene ( PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol. 2002 Aug;104(2):155-70. PubMed.

Other mutations at this position

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