Mutations

APP I716F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275338A>T
Genomic Mutation Name (NT1): g.284034A>T
dbSNP ID: rs1455649881
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: ATC to TTC
Research Models: 2

Findings

This mutation was first detected in a Caucasian patient of Spanish or Portuguese ancestry who was diagnosed with probable Alzheimer's disease according to DSM-IV and NINCDS-ADRDA criteria. Clinical symptoms began at age 31 and the patient died two years later. The patient had a family history of AD, although it was not possible to evaluate segregation of the mutation with disease. The authors suggest that the mutation is likely to be pathogenic given that other pathogenic mutations have been described previously at residue 716 (I716V and I716T) (Guerreiro et al., 2010).

Neuropathology

Postmortem examination revealed neuropathology consistent with a diagnosis of Alzheimer's, namely neurofibrillary changes (Braak stage VI) and amyloid deposits (stage C) (Guerreiro et al., 2010). In another case, an individual with onset at age 31 and death at age 36, Lewy bodies were observed in the amygdala in addition to abundant diffuse amyloid plaques composed mainly of Aβ42 and widespread neurofibrillary pathology (Guardia-Laguarta et al., 2010).

Biological Effect

Many years before this mutation was detected in a patient, an I to F amino acid change at this position was shown experimentally to affect APP cleavage by γ-secretase. Specifically, it was shown that when the isoleucine residue was altered to phenylalanine, the amino acid change, referred to as I45F, affected γ-secretase cleavage specificity and caused a dramatic increase in the the Aβ42/Aβ40 ratio (Lichtenthaler et al., 1999). Consistent with this effect on Aβ production, an elevated Aβ42/Aβ40 ratio was reported in CHO cells as well as increased APP C-terminal fragments and decreased APP intracellular domain production (Herl et al., 2009; Guardia-Laguarta et al., 2010).

Research Models

This mutation has been introduced into several AD mouse models, including two knock-in models (APPNL-F and APPNL-G-F). The presence of the I716F mutation in these models significantly increases the ratio of Aβ42 to Aβ40. These knock-in mice, which also harbor additional APP mutations, develop amyloid plaques, gliosis, and cognitive impairment, but not tangles or neurodegeneration. They are considered advantageous models for studying the effects of pathological levels of Aβ in the context of physiological levels of APP.

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References

Mutations Citations

  1. APP I716V (Florida)
  2. APP I716T

Paper Citations

  1. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  2. . Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation. J Neuropathol Exp Neurol. 2010 Jan;69(1):53-9. PubMed.
  3. . Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3053-8. PubMed.
  4. . Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase. Mol Cell Neurosci. 2009 Jun;41(2):166-74. Epub 2009 Mar 9 PubMed.

Other Citations

  1. APPNL-F

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Other mutations at this position

View Table