Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264090 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACC to CCC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was identified in a 46-year-old Italian patient with early onset AD. She began experiencing memory deficits at the age of 43 and met NINCDS-ADRDA criteria for probable AD. In addition to memory impairment, she also had apraxia and behavioral disturbances. She had a family history of dementia but segregation could not be evaluated. This variant was not detected in 101 unrelated, elderly, cognitively intact controls (Ghidoni et al., 2009), nor was it found in the gnomAD variant database (gnomAD v2.1.1, Oct 2021).

Neuropathology

Neuropathological data are unavailable, but MRI showed atrophy of the temporal lobes, and analysis of cerebral spinal fluid showed reduced total Aβ, especially Aβ1-40 and Aβ1-42, with a relative increase in Aβ1-38 (Ghidoni et al., 2009).

Biological Effect

A survey of Aβ peptides produced from APP carrying this variant, referred to as T48P, revealed an increase in the Aβ49 → Aβ46 → Aβ43 → Aβ40 pathway relative to the Aβ48 → Aβ45 → Aβ42 → Aβ38 processing pathway (Devkota et al., 2021, Feb 2021 news). It also showed inefficient processing of longer, membrane-anchored peptides, resulting in increased levels of Aβ49 and Aβ46. T719P favors ε-cleavage at Aβ49 over Aβ48, without affecting total ε-cleavage activity (Bhattarai et al., 2020; Devkota et al., 2021). Interestingly, the trimming of Aβ46 to Aβ43 from the T48P substrate was nearly abolished, even though Aβ46 produced from this variant lacks the T48P substitution. As described in a subsequent study, this variant, as well as other familial AD variants, appear to 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).

Insights into the molecular underpinnings of these effects have been gleaned from several approaches. Molecular dynamics simulations have shed light on how T719P may shift e-cleavage towards Aβ49 (Bhattarai et al., 2020). Moreover, a bacterial two-hybrid reporter system revealed how alteration of T719 (substituted by an alanine, not a proline) may disrupt critical sites of APP interaction with PSEN1 transmembrane domains 2 and 4, as well as with other APP molecules (Pauli et al., 2023). Also, a cryo-electron microscopy study of an APP fragment bound to PSEN1 indicated T719 helps anchor interactions between the two proteins via hydrogen bonding with PSEN1 G384 (Zhou et al., 2019; Jan 2019 news). Of note, the cryo-EM structure is thought to represent the proteins when they are ready for cleavage, whereas the interactions revealed by the two-hybrid experiments may include earlier binding states (Pauli et al., 2023).

T179P’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. T719P: 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

Paper Citations

Ghidoni R, Albertini V, Squitti R, Paterlini A, Bruno A, Bernardini S, Cassetta E, Rossini PM, Squitieri F, Benussi L, Binetti G. Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides. J Alzheimers Dis. 2009;18(2):295-303. PubMed.
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.
Bhattarai A, Devkota S, Bhattarai S, Wolfe MS, Miao Y. Mechanisms of γ-Secretase Activation and Substrate Processing. ACS Cent Sci. 2020 Jun 24;6(6):969-983. Epub 2020 Jun 4 PubMed.
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.
Pauli TM, Julius A, Costa F, Eschrig S, Moosmüller J, Fischer L, Schanzenbach C, Schmidt FC, Ortner M, Langosch D. Interaction of Substrates with γ-Secretase at the Level of Individual Transmembrane Helices-A Methodological Approach. Int J Mol Sci. 2023 Sep 21;24(18) PubMed.
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.

Mutations

APP T719P

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