Mutations

APP T714I

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264104 C>T
dbSNP ID: rs63750973
Coding/Non-Coding: Coding
Mutation Type: Point, 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 mutation is thought to affect APP processing by γ-secretase and alters the Aβ42/Aβ40 ratio approximately 11-fold, simultaneously increasing Aβ42 and decreasing Aβ40 secretion (Kumar-Singh et al., 2000).

Consistently, a cryo-electron microscopy study of a fragment of APP bound to presenilin 1 suggests T714 is important for the generation of Aβ peptides. Closely apposed to PSEN1 M146, T714 appears to be involved in the recognition of APP by γ-secretase (Zhou et al., 2019; Jan 2019 news). Moreover, 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).

Last Updated: 20 Oct 2021

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . 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. . An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . 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.

Other mutations at this position

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