Mutations

APP D678N (Tottori)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr21:27269917 G>A
dbSNP ID: rs63750064
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAC to AAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

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).

Subsequently, a Caucasian woman initially diagnosed with frontotemporal dementia was found to be a homozygous carrier of this mutation (Mastromoro et al., 2019). Symptoms of primary progressive aphasia were apparent by age 34, although her guardian reported that she began exhibiting speech difficulties and experiencing seizures at age 21. The patient died at age 42 from respiratory complications. This patient had a family history of Alzheimer’s disease: her mother, four maternal uncles, and her maternal grandmother were clinically diagnosed with AD in their 60s; an additional maternal uncle and two aunts were unaffected. Genetic testing led to the suspicion that the patient was the offspring of inbreeding between her mother and one of her mother’s affected brothers. Genotype data were available from only one other family member—the patient’s half-brother on her mother’s side, asymptomatic at age 50, was heterozygous for the mutation. The earlier onset and more rapid disease progression in the proband, compared with other affected family members, suggest a semi-dominant pattern of inheritance.

Neuropathology

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

MRI of the homozygous carrier revealed small lacunar lesions in temporoparietal cortex and subcortical white matter (Mastromoro et al., 2019).

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).

Last Updated: 08 Nov 2019

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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. . Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease. Neurodegener Dis. 2019;19(2):96-100. Epub 2019 Oct 2 PubMed.
  3. . 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.
  4. . 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.
  2. . Effect of the Tottori familial disease mutation (D7N) on the monomers and dimers of Aβ40 and Aβ42. ACS Chem Neurosci. 2013 Nov 20;4(11):1446-57. Epub 2013 Sep 16 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

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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