Mutations

APP D678H (Taiwanese)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1):
Genomic Mutation Name (NT1):
dbSNP ID:
Coding/Non-Coding: Coding
Genomic Region:
Mutation Type: Point, Missense
Codon Change: GAC to CAC

Findings

This mutation was detected in a Taiwanese woman with early onset Alzheimer’s disease. She began to experience progressive memory impairment at the age of 51. Her symptoms also included slurred speech, restlessness, and persecutory delusions. She met NINCDS-ADRDA criteria for probable AD. Her mother and aunt had been affected by cognitive impairment; however, a specific diagnosis was not available. Segregation with disease could not be assessed due to lack of DNA from family members (Chen et al., 2012). This mutation was classified as “probably pathogenic” according to the algorithm proposed by Guerreriro et al., 2010.

Neuropathology

Unknown. SPECT imaging showed hypoperfusion in the bilateral parietal cortices and the left temporal lobe (Chen et al., 2012).

Biological Effect

This mutation alters an amino acid within the Aβ region of APP, specifically the aspartate at the seventh position, which is altered to a histidine (D7H). When expressed in HEK-293 cells, the D678H mutation favors the amyloidogenic pathway and increases production of Aβ40 and Aβ42. Aβ42 is preferentially increased, resulting in an elevated Aβ42/Aβ40 ratio in the conditioned media. In addition, when coincubated with Cu2+ and Zn2+, the mutant Aβ exhibits increased metal ion binding due to the metal-coordinating properties of histidine. The mutant Aβ is also more susceptible to the formation of ion-induced Aβ oligomers and exhibits greater toxicity in vitro compared with wild-type Aβ42 (Chen et al., 2012).

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References

Paper Citations

  1. . Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies. PLoS One. 2012;7(4):e35807. PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

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Primary Papers

  1. . Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies. PLoS One. 2012;7(4):e35807. PubMed.

Other mutations at this position

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