Mutations

APP D678N (Tottori)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.269520G>A
Genomic Mutation Name (NT1): g.278218G>A
dbSNP ID: rs63750064
Coding/Non-Coding: Coding
Genomic Region: Exon 16
Mutation Type: Point, Missense
Codon Change: GAC to AAC

Findings

This mutation was identified in a Japanese pedigree with clinical features consistent with Alzheimer's disease (e.g., progressive dementia without significant cerebrovascular complications) (Wakutani et al., 2004).

Neuropathology

MRI of the proband showed marked cortical and hippocampal atrophy. Focal cerebral infarction and hemorrhagic lesions were absent (Wakutani et al., 2004).

Biological Effect

The D678N mutation alters an amino acid within the Aβ region of APP, specifically at position 7 (D7N). The mutation does not affect Aβ generation from APP (Hori et al., 2007), but does alter the assembly kinetics of the peptide. Mutant Aβ displays accelerated secondary structure transitions and an increased propensity to form relatively large oligomers. The oligomers are also more efficient nucleators of fibril formation, and are significantly more cytotoxic than wild-type peptides (Ono et al., 2010).

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References

Paper Citations

  1. . Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Jul;75(7):1039-42. PubMed.
  2. . The Tottori (D7N) and English (H6R) familial Alzheimer disease mutations accelerate Abeta fibril formation without increasing protofibril formation. J Biol Chem. 2007 Feb 16;282(7):4916-23. PubMed.
  3. . Effects of the English (H6R) and Tottori (D7N) familial Alzheimer disease mutations on amyloid beta-protein assembly and toxicity. J Biol Chem. 2010 Jul 23;285(30):23186-97. PubMed.

Further Reading

Papers

  1. . Gene symbol: APP. Disease: Familial Alzheimer's disease. Hum Genet. 2005 Jul;117(2-3):299. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Jul;75(7):1039-42. PubMed.

Other mutations at this position

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