Mutations

PSEN1 R269G

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37 (105)
Position: Chr14:73664774 C>G
dbSNP ID: rs63751019
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGT to GGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in an individual with a family history of dementia (Perez-Tur et al., 1996). The proband’s father and uncle both died with dementia at 52 and 54 years of age, respectively, and anecdotal evidence suggests the grandfather also suffered from dementia. The proband’s first symptom, emerging at age 47, was memory loss. Other early symptoms included impaired speech fluency and seizures, although clinical evaluation was complicated by alcohol abuse.

The mutation was also found in a pair of siblings, both with an age of symptom onset of 49 years (Doran and Larner, 2004). One presented with depression, followed by obsessiveness and auditory hallucinations. Both individuals had agitation early in the disease, and both developed cognitive decline, seizures, and myoclonus. The mother, who was not genetically tested, developed AD at 79.

Neuropathology
Neuropathological data are unavailable. An MRI scan of one individual showed mild, non-specific cortical atrophy (Doran and Larner, 2004). In this same individual, EEG revealed a moderate, bilateral excess of slow wave activity, and SPECT imaging, 2.5 years after symptom onset, showed non-specific, moderate hypoperfusion of the posterior parietal cortex.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it decreases both Aβ40 and Aβ42 production, and increases the Aβ42/Aβ40 ratio (Sun et al., 2017).

Last Updated: 18 Apr 2019

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References

Paper Citations

  1. . A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration. 1996 Sep;5(3):207-12. PubMed.
  2. . Prominent behavioural and psychiatric symptoms in early-onset Alzheimer's disease in a sib pair with the presenilin-1 gene R269G mutation. Eur Arch Psychiatry Clin Neurosci. 2004 Jun;254(3):187-9. PubMed.
  3. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration. 1996 Sep;5(3):207-12. PubMed.

Other mutations at this position

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