Mutations Position Table
APP E693 Mutations
| Mutation | Pathogenicity | DNA Change | Expected RNA | Protein Consequence | Coding/Non-Coding | Genomic Region | Neuropathology | Biological Effect | Primary Papers |
|---|---|---|---|---|---|---|---|---|
| E693K (Italian) |
CAA : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, cortical calicifications; Aβ immunoreactivity in vessel walls and neuropil; Absence of neurofibrillary changes and neuritic plaques. |
Although reduced Aβ42/Aβ40 ratio and decreased Aβ42, the mutant peptide is toxic in cells and aggregates faster. |
Tagliavini et al., 1999; Bugiani et al., 2010 |
| E693Q (Dutch) |
CAA : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Extensive amyloid deposition in the cerebral vasculature; Hemorrhages; Some diffuse plaques in brain parenchyma. |
Accelerates Aβ aggregation in vitro, increasing fibril formation; may alter APP processing. |
Levy et al., 1990; Van Broeckhoven et al., 1990; Fernandez-Madrid et al., 1991 |
| E693G (Arctic, E22G) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Neuropathology consistent with AD in several carriers. Plaques have a "targetoid: shape, with heterogenous truncated Aβ peptides in the center surrounded by Aβ42. Very low cortical PiB retention. No hemorrhage, but severe congophilic angiopathy. |
Increased propensity to form protofibrils, and at a faster rate. Aβ40 and Aβ42 production reduced or unchanged; increased Aβ5-29 and Aβ5-33. Decreased proteolytic degradation of Aβ by neprilysin. Neuronal toxicity. |
Kamino et al., 1992; Nilsberth et al., 2001 |
| E693del (Osaka, E693∆, E693delta) |
AD : Pathogenic | Deletion | Deletion | Deletion | Coding | Exon 17 | Unknown; remarkably low levels of amyloid by PiB-PET imaging in multiple carriers, but high tau-PET signal in one case. |
Enhanced oligomerization and nucleation of Aβ aggregates in vitro; altered production, secretion, localization, and clearance of Aβ peptides in cells; cognitive impairment, synaptic deficits, neuronal loss, glial activation, and tau hyperphosphorylation in animal models. |
Tomiyama et al., 2008 |
| F690_V695del (Uppsala deletion, APP Δ690-695, APP delta690–695, Uppsala APP deletion) |
AD : Pathogenic | Deletion | Deletion | Deletion | Coding | Exon 17 | One reported carrier of this variant had autopsy-confirmed AD. |
Appears to largely eliminate non-amyloidogenic processing of APP and leads to the generation of rapidly aggregating Aβ peptides lacking amino acids 19-24. In mice, Aβ fibrils barely evoke a glial response. |
Pagnon de la Vega et al., 2021 |
Within codon 693 of APP three pathogenic missense mutations have been identified and one deletion mutation that removes the entire codon and results in an APP protein that lacks an amino acid. The wild-type codon codes for glutamate at this position, which falls within the Aβ region of APP. The clinical phenotype of mutation carriers at this position varies. Some mutations (E693Q-Dutch and E693K-Italian) lead to cerebral amyoid angiopathy characterized by severe amyloid accumulation in cerebral blood vessel walls and some parenchymal amyloid plaques. Other mutations (E693G-Arctic and E693del) present with features more consistent with AD. In cell culture, these mutations tend to produce lower levels of secreted Aβ42 than wild-type APP, with minimal effect on Aβ40 levels, resulting in an overall decreased Aβ42/Aβ40 ratio (for example, see Nilsberth et al., 2001).
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