Mutations

APP A692G (Flemish)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275267C>G
Genomic Mutation Name (NT1): g.283963C>G
dbSNP ID: rs63750671
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GCA to GGA

Findings

This mutation was first reported in a four-generation Flemish pedigree. Affected individuals were diagnosed with Alzheimer's disease or cerebral hemorrhage associated with Cerebral Amyloid Angiopathy. The mean age at onset in this family was 45.7 ± 7.3 years (Hendriks et al., 1992).

A second pedigree of three generations was reported with five affected individuals. Dementia was the primary clinical feature in these patients. The proband also had a cerebral hemorrhage, but other affected family members did not. Neuropathologic examination confirmed AD, congophilic angiopathy, and hemorrhagic infarction. In this family, dementia onset ranged from 39 to 54 years (Brooks et al.,  2004).

Neuropathology

The Flemish mutation is associated with variable pathology, but generally involves amyloid deposition in the blood vessels of the brain. Numerous senile plaques were also observed that were described as large Aβ amyloid cores, often more than 30 microns in diameter and surrounded by dystrophic neurites (Cras et al., 1998).

Biological Effect

This mutation increased secreted Aβ42 and Aβ40 in CHO, HEK-293, and H4 cells approximately 2- to 4-fold (Haass et al., 1994; De Jonghe et al., 1998). This region of APP, specifically, the amino acid sequence LVFFAED, has been shown to inhibit the activity of γ-secretase (Tian et al., 2010). Deletion of this sequence resulted in a 10-fold increase in secreted Aβ40. The inhibitory effect of this region is attenuated by the Flemish mutation, which causes structural changes in the extracellular sequence LVFFAEDVGSNK leading to a reduction of inhibitory interactions and influencing the dimerization of the transmembrane helix (Tang et al., 2014).

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References

Paper Citations

  1. . Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):218-21. PubMed.
  2. . Hemorrhage is uncommon in new Alzheimer family with Flemish amyloid precursor protein mutation. Neurology. 2004 Nov 9;63(9):1613-7. PubMed.
  3. . Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation. Acta Neuropathol. 1998 Sep;96(3):253-60. PubMed.
  4. . Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. J Biol Chem. 1994 Jul 1;269(26):17741-8. PubMed.
  5. . Flemish and Dutch mutations in amyloid beta precursor protein have different effects on amyloid beta secretion. Neurobiol Dis. 1998 Oct;5(4):281-6.
  6. . An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production. Nat Struct Mol Biol. 2010 Feb;17(2):151-8. PubMed.
  7. . Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased Aβ production. Structure. 2014 Mar 4;22(3):387-96. Epub 2014 Jan 23 PubMed.

Further Reading

Papers

  1. . Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain. 2000 Oct;123 ( Pt 10):2130-40. PubMed.
  2. . Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric. Am J Pathol. 2002 Aug;161(2):507-20. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):218-21. PubMed.