Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891789 T>C
Position: (GRCh37/hg19):Chr21:27264101 T>C
dbSNP ID: rs63750868
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to GCG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation, near the γ-secretase cleavage site in APP, was first reported in a German pedigree. The proband was a 50-year-old woman with a family history of dementia consistent with autosomal-dominant inheritance. She demonstrated progressive cognitive impairment and fulfilled NINCDS-ADRDA criteria for probable Alzheimer's disease. The mean age of onset for the four affected members of this family was 52 years (Cruts et al., 2003).  

This mutation was also found in a female patient in Poland who met NINCDS-ADRDA criteria for probable Alzheimer's disease with significant impairment of verbal memory and decline in visuospatial functioning. Symptoms started at age 42. Family history was unavailable (Zekanowski et al., 2003).

The V715A mutation was also found in a large French study reporting 56 new families with autosomal-dominant, early onset Alzheimer’s disease. All probands met NINCDS-ADRDA criteria for probable AD and had a family history of disease (Wallon et al., 2012). The V715A mutation was detected in one individual in a family known as EXT 147, which had 10 known affected family members. Only the genotype of the proband is known, therefore segregation with disease could not be determined. Age of onset in this family ranged from 40 to 44 years of age, with a six- to 13-year disease course. The mutation was classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

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

Neuropathology

PET imaging showed hypoperfusion in the parieto-occipital region (Cruts et al., 2003).

Biological Effect

This mutation increased the Aβ42/Aβ40 ratio approximately fourfold in HEK293 cells (Cruts et al., 2003). A similar increase was observed in primary neuronal cultures, with a decrease in Aβ40 and an increase in Aβ42 (De Jonghe et al., 2001). Moreover, drastically increased Aβ42/40 and Aβ38/40 ratios, as well as a total inhibition of the production of the APP intracellular domain fragment AICD50–99, were observed in cell-free assays (Chávez-Gutiérrez et al., 2012, Dimitrov et al., 2013). This indicated an increase in the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway relative to the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway.

A subsequent study using NMR spectroscopy suggested a mechanism in which V715A destabilizes the local helical conformation of both T48 and L49 ε-cleavage sites (Chen et al., 2014). Because the destabilization is stronger at the T48 site, making it more accessible for cleavage than the L49 site, production of Aβ peptides was expected to be shifted towards the Aβ48 pathway, increasing Aβ42 levels. A comprehensive analysis of all Aβ peptides generated from V715A was consistent with this prediction, showing an increase in all Aβ peptides, but particularly those in the Aβ48 pathway (Devkota et al., 2021, Feb 2021 news). Also, this study showed the mutation led to inefficient trimming of Aβ, resulting in increased levels of longer, membrane-anchored peptides that may be pathogenic.

A cryo-electron microscopy study of a fragment of APP bound to presenilin 1 suggests V715 is closely apposed to PSEN1's hydrophobic residue W165, one of PSEN1's sparse interactions with the lipid-exposed APP transmembrane helix (Zhou et al., 2019; Jan 2019 news). Moreover, a study using molecular dynamics simulations suggested V715 and I716 serve to anchor APP at the PSEN1 internal docking site, a region distinct from the catalytic center, that is essential for substrate positioning and stabilization (Chen and Zacharias 2022).

The T714A variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

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.

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References

News Citations

1. Are the Long Aβ Peptides the Real Bad Guys? 5 Feb 2021
2. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Cruts M, Dermaut B, Rademakers R, Van den Broeck M, Stögbauer F, Van Broeckhoven C. Novel APP mutation V715A associated with presenile Alzheimer's disease in a German family. J Neurol. 2003 Nov;250(11):1374-5. PubMed.
2. Zekanowski C, Styczyńska M, Pepłońska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haładyna B, Kotapka-Minc S, Mikkelsen S, Pfeffer A, Barczak A, Łuczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Łaczkowski J, Sobów T, Kuźnicki J, Barcikowska M. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
3. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
4. De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B. Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001 Aug 1;10(16):1665-71. PubMed.
5. Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, De Strooper B. The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
6. Dimitrov M, Alattia JR, Lemmin T, Lehal R, Fligier A, Houacine J, Hussain I, Radtke F, Dal Peraro M, Beher D, Fraering PC. Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat Commun. 2013;4:2246. PubMed.
7. Chen W, Gamache E, Rosenman DJ, Xie J, Lopez MM, Li YM, Wang C. Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site. Nat Commun. 2014;5:3037. PubMed.
8. Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
9. 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.
10. Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.

Further Reading