Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27269890 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAA to AAT
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16

Findings

The K687N mutation results in an amino acid substitution at the α-secretase cleavage site in APP. The mutation was described in an individual affected by a form of early onset dementia consistent with Alzheimer’s disease. The patient presented with progressive deficits across several cognitive domains, including short-term memory, mathematical ability, and verbal fluency. He had a family history of dementia; the reported pedigree shows six affected individuals over three generations. Segregation with disease could not be assessed due to lack of DNA from family members. The mutation was absent in 500 healthy individuals. PSEN1, PSEN2, and PRNP genes were also screened; no additional mutations were found (Kaden et al., 2012).

This variant was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology

Unknown. MRI showed mild global brain atrophy without focal or vascular lesions. CSF analysis revealed a biomarker profile consistent with AD, specifically elevated total tau and phosphorylated tau, along with reduced levels of Aβ1-42.

Biological Effect

In vitro, this mutation makes APP a poor substrate for cleavage by α-secretase, with reduced production of total sAPP, and especially sAPPα. In contrast, levels of Aβ40 and Aβ42 are elevated. This mutation affects an amino acid within the Aβ region of APP, specifically the lysine at position 16, which is mutated to arginine (K16N). Although mutations in the Aβ region typically enhance Aβ toxicity,  the Aβ42 K16N peptide was less harmful to neuroblastoma cells than wild-type Aβ42. However, the mutant peptide was highly toxic when mixed in equimolar amounts with wild-type Aβ, the expected situation in a patient heterozygous for the mutation. Similarly, although the mutant Aβ peptide formed predominantly low-n oligomers in vitro, when mixed with  wild-type Aβ it aggregated into high-n oligomers. The Aβ K16N peptide was also much less efficiently degraded by neprilysin (Kaden et al., 2012).

K687 is evolutionarily conserved and a structural model predicted the K687N substitution impairs the interaction between APP and nicastrin in the γ-secretase complex (Liang et al., 2023). Consistent with these findings, this variant's PHRED-scaled CADD score was above 20, suggesting a damaging effect (CADD v1.6, 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

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References

Paper Citations

1. Kaden D, Harmeier A, Weise C, Munter LM, Althoff V, Rost BR, Hildebrand PW, Schmitz D, Schaefer M, Lurz R, Skodda S, Yamamoto R, Arlt S, Finckh U, Multhaup G. Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers. EMBO Mol Med. 2012 Jul;4(7):647-59. PubMed.
2. Liang Z, Wu Y, Li C, Liu Z. Clinical and genetic characteristics in a central-southern Chinese cohort of early-onset Alzheimer's disease. Front Neurol. 2023;14:1119326. Epub 2023 Mar 27 PubMed.

Further Reading

No Available Further Reading