Mutations

APP I716T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891786 T>C
Position: (GRCh37/hg19):Chr21:27264098 T>C
dbSNP ID: rs63750851
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to ACC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was reported in an abstract from the eighth International Conference on Alzheimer's, held 20-25 July 2002. The abstract described the detection of the I716T mutation in one individual with early onset Alzheimer’s disease. Symptoms began at age 36. The patient developed progressive memory decline and psychomotor symptoms. AD was reported to run in the family, but further details were not provided in the abstract. The patient died at the age of 43 (Terreni et al., 2002). 

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

Neuropathology

Nueropathological data are unavailable.

Biological Effect

This variant has been reported to affect γ-secretase cleavage of APP at both ε- and γ-sites, resulting in reduced production of Aβ peptides and the APP intracellular domain (AICD), as well as alterations in the relative Aβ peptide levels (Chávez-Gutiérrez et al., 2012, Xu et al., 2016, Bolduc et al., 2016, Devkota et al., 2021). Overall, ε-cleavage is reduced and shifted towards the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway. Increased H-bond stability, resulting in decreased flexibility of the ε-cleavage sites, may contribute to the reduction (Götz et al., 2019). Moreover, I716T causes a relative accumulation of longer Aβ peptides, including Aβ49, a membrane-anchored peptide that may be pathogenic (Chávez-Gutiérrez et al., 2012, Devkota et al., 2021, Feb 2021 news), and an increased Aβ42/Aβ40 ratio (Xu et al., 2016, Bolduc et al., 2016). Because I716T maps to position 45 in the Aβ peptide, often referred to as I45T, it also appears to interfere with the trimming of Aβ45 → Aβ42, resulting in an increased Aβ38/Aβ42 ratio (Chávez-Gutiérrez et al., 2012).

The interaction of the V715-I716 segment of APP with the catalytic unit of γ-secretase, PSEN1, has been described in a cryo-electron microscopy study, including how it differs from that of PSEN1 with the Notch substrate (Zhou et al., 2019; Jan 2019 news). Also, a study using molecular dynamics simulations suggested I716, together with V715, 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).

Also of note, I45T may stall the γ-secretase-substrate complex and the presence of this membrane-anchored complex per se may be toxic (Devkota et al., 2024; Nov 2023 news). 

This 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 : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. I716T: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 14 Feb 2024

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References

News Citations

  1. Are the Long Aβ Peptides the Real Bad Guys?
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  3. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase

Paper Citations

  1. Terreni L, Fogliarino S, Franceschi M, Forloni G. Novel pathogenic mutation in an Italian patient with familial Alzheimer's disease detected in APP gene. Neurobiol Aging. 2002 Jul-Aug;23(1S):319.
  2. 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.
  3. Xu TH, Yan Y, Kang Y, Jiang Y, Melcher K, Xu HE. Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to γ-secretase cleavage and the Aβ42/Aβ40 ratio. Cell Discov. 2016;2:16026. Epub 2016 Aug 23 PubMed.
  4. Bolduc DM, Montagna DR, Seghers MC, Wolfe MS, Selkoe DJ. The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase. Elife. 2016 Aug 31;5 PubMed.
  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. Götz A, Högel P, Silber M, Chaitoglou I, Luy B, Muhle-Goll C, Scharnagl C, Langosch D. Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer's Disease Mutant of APP. Sci Rep. 2019 Mar 29;9(1):5321. PubMed.
  7. 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.
  8. 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.
  9. Devkota S, Zhou R, Nagarajan V, Maesako M, Do H, Noorani A, Overmeyer C, Bhattarai S, Douglas JT, Saraf A, Miao Y, Ackley BD, Shi Y, Wolfe MS. Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 27;43(2):113761. Epub 2024 Feb 13 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Terreni L, Fogliarino S, Franceschi M, Forloni G. Novel pathogenic mutation in an Italian patient with familial Alzheimer's disease detected in APP gene. Neurobiol Aging. 2002 Jul-Aug;23(1S):319.

Other mutations at this position

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Alzpedia

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