Mutations

APP T714A

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264105 A>G
dbSNP ID: rs63750643
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACA to GCA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation was first reported in a three-generation Iranian pedigree with nine documented affected individuals and an average age of onset of approximately 55 years. The common feature of all the affected members of this family was progressive dementia consistent with AD, although motor apraxia was also observed in some cases. The reporting authors noted that the age at onset in this family was considerably older than the age reported for APP T714I, presumably because alanine causes less disruption to the transmembrane structure than isoleucine (Pasalar et al., 2002). The mutation was identified in two affected siblings and was absent from an unrelated, healthy individual.

This mutation has been found in two additional studies. One was a Polish individual with Alzheimer's disease. In this patient, onset was at 44 years and the disease progressed rapidly, leading to severe memory impairment and other cognitive and behavioral deficits within four years (Zekanowski et al., 2003). A different clinical picture was associated with this mutation in another, unrelated individual who was diagnosed with AD following a long prodromal phase (eight years of isolated amnesia). The clinical presentation in this individual was atypical in that it was also characterized by autonomic failure and seizures (Lindquist et al., 2008).

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

Neuropathology

The neuropathology associated with this mutation is not well characterized, but neuroimaging in one patient showed progressive cortical atrophy and white matter lesions (Lindquist et al., 2008).

Biological Effect

The biological effect of this variant is unknown, but 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: 19 Oct 2021

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References

News Citations

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

Paper Citations

  1. . An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). Neurology. 2002 May 28;58(10):1574-5. PubMed.
  2. . Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003 Dec;184(2):991-6. PubMed.
  3. . Atypical early-onset Alzheimer's disease caused by the Iranian APP mutation. J Neurol Sci. 2008 May 15;268(1-2):124-30. PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

Papers

  1. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.

Protein Diagram

Primary Papers

  1. . An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). Neurology. 2002 May 28;58(10):1574-5. PubMed.

Other mutations at this position

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