Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891792 C>T
Position: (GRCh37/hg19):Chr21:27264104 C>T
dbSNP ID: rs63750973
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to ATA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 2

Findings

This mutation involves amino acid position 714 in APP and is located at a site of γ-secretase cleavage. It was first reported in an Austrian family known as AD156 whose members displayed an autosomal-dominant form of early onset Alzheimer's disease. This mutation appears to produce a particularly aggressive form of AD that had a mean onset age of approximately 34 years in the Austrian family (Kumar-Singh et al., 2000). Two affected siblings carried the mutation, but not their unaffected father, indicating cosegregation with disease.

This mutation was also identified in an American kindred of African descent. Affected family members were diagnosed with AD with an unusually early onset (early 30s), similar to that reported in the Austrian family. Clinical findings for this family included a rapidly progressive dementia with early memory loss, seizures, myoclonus, parkinsonism, spasticity, and behavioral symptoms including pathologic laughter (Edwards-Lee et al., 2005).

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

Neuropathology

Postmortem analysis of members of the Austrian family showed extensive neuronal loss, diffuse gliosis, and amyloid plaques and neurofibrillary tangles consistent with a diagnosis of AD. Aβ40 was notably absent from amyloid deposits in the brain, and the deposits were largely in the form of "cloudy" diffuse plaques with a non-neuritic cotton-wool appearance (Kumar-Singh et al., 2000).

Biological Effect

This variant, a.k.a. as T43I based on its position in the Aβ peptide, increases the Aβ42/Aβ40 ratio approximately 11-fold, simultaneously increasing Aβ42 and decreasing Aβ40 secretion (Kumar-Singh et al., 2000). A subsequent study confirmed the increase in Aβ42/Aβ40 and also showed an increase in Aβ38 and the Aβ38/Aβ40 ratio, as well as abrogation of ε-cleavage resulting in AICD50-99 and Aβ49 (Dimitrov et al., 2013).  Consistent with these findings, two studies that surveyed AICD and Aβ production in vitro, indicated an increase in the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway relative to the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway, as well as inefficient processing of longer forms of Aβ, resulting in increased levels of membrane-anchored, and potentially pathogenic peptides, particularly Aβ48 (Szaruga et al., 2017, Devkota et al., 2021, Feb 2021 news). 

Several studies have provided clues of the underlying mechanisms (Dimitrov et al., 2013, Szaruga et al., 2017, Tang et al., 2019, Suzuki et al., 2023, Koch et al., 2023). Szaruga and colleagues, for example, reported the T43I substitution resulted in temperature-sensitive destabilization of enzyme-substrate complexes, leading to the dissociation and release of long Aβ peptides (Szaruga et al., 2017). Interestingly, replacing hydrophylic lysine at position 28 with hydrophobic alanine in T43I peptides increased the proportion of shorter peptides and reduced Aβ42 levels (Koch et al., 2023, Nov 2023 news). The authors speculated K28A rescued substrate-enzyme destabilization by pushing the peptide further into the membrane, counteracting the hydrophilic pull of its N-terminus.

Also of note, molecular dynamics simulations predicted a shift of the transmembrane helix that harbors T714I which could explain changes in APP’s interaction with γ-secretase and consequent changes in Aβ and AICD production (Dimitrov et al., 2013). Moreover, NMR spectroscopy analysis indicated T714I increases helical structure and helical tilt (Tang et al., 2019).

A cryo-electron microscopy study of a fragment of APP bound to PSEN1 suggested T714 is closely apposed to PSEN1 M146, and likely involved in the recognition of APP by γ-secretase (Zhou et al., 2019; Jan 2019 news).

T714A'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. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase 17 Nov 2023
3. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Kumar-Singh S, De Jonghe C, Cruts M, Kleinert R, Wang R, Mercken M, De Strooper B, Vanderstichele H, Löfgren A, Vanderhoeven I, Backhovens H, Vanmechelen E, Kroisel PM, Van Broeckhoven C. Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease. Hum Mol Genet. 2000 Nov 1;9(18):2589-98. PubMed.
2. Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. PubMed.
3. 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.
4. Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L. Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
5. 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.
6. Tang TC, Kienlen-Campard P, Hu Y, Perrin F, Opsomer R, Octave JN, Constantinescu SN, Smith SO. Influence of the familial Alzheimer's disease-associated T43I mutation on the transmembrane structure and γ-secretase processing of the C99 peptide. J Biol Chem. 2019 Apr 12;294(15):5854-5866. Epub 2019 Feb 12 PubMed.
7. Suzuki R, Takahashi H, Yoshida C, Hidaka M, Ogawa T, Futai E. Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production. Int J Mol Sci. 2023 Feb 16;24(4) PubMed.
8. Koch M, Enzlein T, Chen SY, Petit D, Lismont S, Zacharias M, Hopf C, Chávez-Gutiérrez L. APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release. EMBO J. 2023 Dec 1;42(23):e114372. Epub 2023 Oct 18 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.

Further Reading

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