Mutations Position Table

APP E693 Mutations

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
E693del
(Osaka, E693∆, E693delta)
Alzheimer's Disease Alzheimer's Disease : Pathogenic

Unknown; remarkably low levels of amyloid by PiB-PET imaging.

Unchanged Aβ42/Aβ40 ratio; decreased Aβ42; decreased Aβ40; Mutant Aβ more resistant to degradation by neprilysin and insulin-degrading enzyme; Synthetic mutant Aβ had enhanced oligomerization but no fibrillization; Greater inhibition of LTP than wild-type Aβ.


Coding
Exon 17
Deletion
GAA to ---
1 Tomiyama et al., 2008
E693G
(Arctic, E22G)
Alzheimer's Disease Alzheimer's Disease : Pathogenic

No signs of strokes or vascular lesions by brain imaging; Neuritic plaques and neurofibrillary tangles.

Arctic Aβ40 forms protofibrils at an increased propensity and faster rate; Decreased proteolytic degradation of Aβ by neprilysin.

rs63751039
Coding
Exon 17
Point, Missense
GAA to GGA
5 Kamino et al., 1992;
Nilsberth et al., 2001
E693K
(Italian)
Cerebral Amyloid Angiopathy Cerebral Amyloid Angiopathy : Pathogenic

Small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts; Aβ immunoreactivity in vessel walls and neuropil; Absence of neurofibrillary changes and neuritic plaques.

Reduced Aβ42/Aβ40 ratio; decreased Aβ42; comparable Aβ40 to wild-type APP.

rs63750579
Coding
Exon 17
Point, Missense
GAA to AAA
0 Tagliavini et al., 1999;
Bugiani et al., 2010
E693Q
(Dutch)
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type Cerebral Amyloid Angiopathy : Pathogenic

Extensive amyloid deposition in the cerebral vasculature; Hemorrhages; Some diffuse plaques in brain parenchyma.

Accelerates Aβ aggregation in vitro, increasing fibril formation; Alters the processing of APP, increasing the relative quantities of Aβ beginning at Asp1, Val18, and Phe19.

rs63750579
Coding
Exon 17
Point, Missense
GAA to CAA
4 Levy et al., 1990;
Van Broeckhoven et al., 1990;
Fernandez-Madrid et al., 1991

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).