Mutations

APP M722K

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr21:25891768 T>A
Position: (GRCh37/hg19):Chr21:27264080 T>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to AAG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation in APP was reported in a Chinese family affected by early onset Alzheimer’s disease (Wang et al., 2015). The proband developed memory problems at the age of 38 and met NINCDS-ADRDA criteria for AD by age 42. The reported pedigree shows four additional affected family members over three generations. Symptoms were typical for AD, e.g., decline in memory and executive functioning, as well as depression. There was a strong family history, but the mutation could not be shown conclusively to segregate with disease. It was absent in an unaffected sibling (age 58), but present in another unaffected sibling (age 42). The authors speculate that the unaffected mutation carrier may be presymptomatic.

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

Neuropathology

Unknown. MRI of the proband at age 42 showed moderate cerebral atrophy, especially in the hippocampus.

Biological Effect

N2a neuroblastoma cells expressing APP (isoform 695) with the M722K mutation had elevated levels of Aβ42 in conditioned media and cell lysates compared with cells expressing wild-type APP. Differences in Aβ40 were not significant. There was a 1.7-fold increase in the Aβ42/Aβ40 ratio compared to cells expressing wild-type APP. In addition, cells expressing the mutant APP also had more phospho-tau as detected by the AT8 antibody.

A cryo-electron microscopy study of an APP fragment bound to PSEN1 revealed that M722 is part of a short stretch of amino acids next to the γ-secretase cleavage site that adopt a β-strand conformation upon binding to PSEN1 (Zhou et al., 2019; Jan 2019 news).

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-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M722K: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

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

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. Wang Q, Jia J, Qin W, Wu L, Li D, Wang Q, Li H. A Novel AβPP M722K Mutation Affects Amyloid-β Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals. J Alzheimers Dis. 2015;47(1):157-65. PubMed.
  2. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Wang Q, Jia J, Qin W, Wu L, Li D, Wang Q, Li H. A Novel AβPP M722K Mutation Affects Amyloid-β Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals. J Alzheimers Dis. 2015;47(1):157-65. PubMed.

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