Mutations Position Table
APP V717 Mutations
| Mutation | Pathogenicity | DNA Change | Expected RNA | Protein Consequence | Coding/Non-Coding | Genomic Region | Neuropathology | Biological Effect | Primary Papers |
|---|---|---|---|---|---|---|---|---|
| V717F (Indiana) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | In one case, neuropathology was consistent with AD. |
In vitro, increased long Aβ peptides (Aβ48, 46, 45), ε-cleavage, Aβ48 pathway. In cells, increased Aβ42/Aβ40 ratio. Altered endocytosis and transport of lipoproteins and APP to axons, possibly via increased β-CTF. |
Murrell et al., 1991 |
| V717I (London) |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Variable: AD plaques and tangles with some reports of mild to severe CAA, cortical and brainstem Lewy bodies, TDP-43 pathology in hippocampus and amygdala, striatal amyloid deposition. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; little effect on Aβ40. In yeast system, reduced ε-cleavage. |
Goate et al., 1991 |
| V717L |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Unknown; MRI in the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices. |
Increased total Aβ, Aβ42, Aβ42/Aβ40 ratio; decreased Aβ40. Increased Aβ48 → Aβ45 → Aβ42 → Aβ38 pathway; decreased Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway. Inefficient processing of longer, membrane-anchored peptides: increases in Aβ48, Aβ46, and Aβ45. ε-cleavage also increased. |
Murrell et al., 2000 |
| V717G |
AD : Pathogenic | Substitution | Substitution | Missense | Coding | Exon 17 | Neuropathology consistent with AD in at least one case. |
Increased Aβ42/Aβ40 ratio; increased total Aβ, Aβ48, Aβ46, Aβ45, Aβ42, and Aβ38; decreased Aβ40. Increased long, membrane-anchored Aβ peptides. Increased ε-cleavage, including cleavage at a novel site. |
Chartier-Harlin et al., 1991 |
There are four missense mutations reported for codon 717 of APP. Three of these were the first mutations in APP to be linked with early-onset Alzheimer's disease and were an important early demonstration of the significance of the APP gene to the development of AD. Specifically, in 1991 the V717I (Goate et al., 1991), V717F (Murrell et al., 1991) and V717G (Chartier Harlin et al., 1991) mutations were described for the first time. The amino acid corresponding to codon 717 is within the intramembrane region of APP near the γ-secretase site. Although this amino acid is not within the Aβ region, mutations at this position alter the relative levels of Aβ peptides, including increasing the Aβ42/Aβ40 ratio.
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