Mutations

APP T719P

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264090 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACC to CCC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation (g.26453775 A>C NC_000021.7) was first 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

The biological effects of this variant are unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). Moreover, 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). 

Last Updated: 21 Oct 2021

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References

News Citations

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

Paper Citations

  1. . Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides. J Alzheimers Dis. 2009;18(2):295-303. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides. J Alzheimers Dis. 2009;18(2):295-303. PubMed.

Other mutations at this position

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