Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25897605 G>A
Position: (GRCh37/hg19):Chr21:27269917 G>A
dbSNP ID: rs63750064
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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). The proband's age at onset was approximately 60 years. She and a sibling who was also demented carried the mutation, whereas a nephew who was unaffected at age 68 did not, suggesting cosegregation with disease.

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, raise the possibility of a semi-dominant pattern of inheritance.

This variant was absent from the gnomAD database (V2.1.1, Oct 2021).

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).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. D678N: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 22 Feb 2022

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References

Paper Citations

Wakutani Y, Watanabe K, Adachi Y, Wada-Isoe K, Urakami K, Ninomiya H, Saido TC, Hashimoto T, Iwatsubo T, Nakashima K. 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.
Mastromoro G, Gambardella S, Marchionni E, Campopiano R, Traversa A, Di Bonaventura C, Pizzuti A. Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease. Neurodegener Dis. 2019;19(2):96-100. Epub 2019 Oct 2 PubMed.
Hori Y, Hashimoto T, Wakutani Y, Urakami K, Nakashima K, Condron MM, Tsubuki S, Saido TC, Teplow DB, Iwatsubo T. 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.
Ono K, Condron MM, Teplow DB. 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.

Mutations

APP D678N (Tottori)

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