Mutations

APP A713T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, None
Genome Build: 105
Position: Chr21:27264108 G>A
dbSNP ID: rs63750066
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GCG to ACG

Findings

This mutation is associated with a variable phenotype. Some mutation carriers exhibit clinical and neuropathological features typical of Alzheimer's disease, while others have a more complex presentation, with prominent cerebrovascular disease and cerebral amyloid angiopathy (CAA). Unaffected mutation carriers also have been documented (Carter et al., 1992).

A French study first reported this mutation in one of 130 people with probable AD, according to NINCDS-ADRDA criteria. The mutation carrier was a 64-year-old woman who experienced memory loss at age 59. She did not have a family history of dementia. The mutation was also detected in five unaffected relatives, including three over the age of 62, arguing against segregation with disease, although incomplete penetrance was offered as another potential explanation. In this family, the A713T G>A mutation was accompanied by a second G>A transition at codon 715, predicted to be silent. Because of the proximity of the two point mutations, the authors described their finding as a double point mutation (GCG.ACA.GTG to ACG.ACA.GTA) (Carter et al., 1992).

The A713T mutation was later reported in an Italian family affected by autosomal dominant AD and strokes (Rossi et al., 2004). The reported pedigree shows six individuals over three generations. DNA was available from three affected family members, and all were heterozygous carriers, suggesting segregation with disease. For the three affected family members for whom details were known, onset ranged from 52 to 68 years of age, with death at 57 to 73 years. The proband developed cognitive decline at age 52 and also experienced stroke-like symptoms, such as temporary language disturbances and monoparesis, the partial loss of voluntary movement in a single limb. Autopsy showed features consistent with a diagnosis of AD, including widespread amyloid plaques and neurofibrillary tangles (Braak stage VI). CAA was also prominent.

Also in 2004, a Spanish group reported the A713T mutation in a 56-year-old-man with a seven-year history of progressive cognitive decline consistent with AD. His first symptoms were memory impairment and depression. His older brother was also affected by dementia, but a detailed family history was not reported, and segregation with disease could not be established (Armstrong et al., 2004).

Most recently the A713T mutation was discovered in a large Italian family with both heterozygous and homozygous mutation carriers (Conidi et al., 2015). The pedigree of the “PEC family” shows eight affected individuals over six generations. This family is not known to be genealogically connected to other A713T pedigrees, but the authors speculate that the Italian families are most likely related based on haplotype analysis. Disease in this family was described as AD with cerebrovascular lesions. Three affected family members were shown to be homozygous for the mutation and two were heterozygous. Genotype did not affect onset age, which was comparable between heterozygotes (e.g., 62, 73) and homozygotes (e.g. 76, 70, 70). The mutation was absent in 400 control individuals from the same region of Italy.

Neuropathology

The neuropathology associated with the A713T mutation is variable. Some cases accumulate pathology fairly typical of AD, notably atrophy of the cerebral cortex, and especially the temporal lobes, with widespread neurofibrillary tangles and amyloid plaques and minimal amyloid angiopathy (e.g., Armstrong et al., 2004). However, other cases exhibit prominent vascular involvement with prominent CAA and other vascular lesions (e.g., Rossi et al., 2004Bernardi et al., 2009Conidi et al., 2015).

Biological Effect

In postmortem brain there was no change in the Aβ42/Aβ40 ratio (Armstrong et al., 2004). However, the plasma Aβ42/Aβ40 ratio was higher in asymptomatic mutation carriers than in non-mutation carrying relatives, due to a decrease in Aβ40 and an increase in Aβ42. In silico, the A713T mutation is predicted to be damaging and disease-causing (Conidi et al., 2015).

Comments

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Comments on this content

  1. We found that the A713T mutation segregated with disease in a large Italian family, strongly supporting the pathogenicity of this rare variant (Conidi et al., 2015). However, this mutation did not segregate with disease in a previously described family (Carter et al., 1992). Although we can only speculate, it may be that the four “healthy” A713T carriers in that family were, in fact, presymptomatic at age 62 and older (and in one case at age 88). Other studies have shown that carriers of this mutation exhibit a particularly variable age of symptom onset , ranging from 52 to 82 years (Rossi et al., 2004; Bernardi et al., 2009). It is also possible, as Carter and colleagues suggested, that genetic, epigenetic or environmental modifiers influence the penetrance of the A713T mutation.

    Of particular note, in the A713T family they studied, Carter and colleagues also detected a G>A transition in the codon for the nearby amino acid 715. This is a synonymous change and may simply be a rare polymorphism. It was not present in the Italian family we studied, nor reported in any of the other known A713T carriers. Given the apparent lack of segregation of A713T in the family studied by Carter, it is possible that the accompanying G>A transition at codon 715 may reduce the penetrance of the A713T mutation. It is increasingly recognized that “silent” mutations can have significant biological effects, and that synonymous codons are not necessarily equivalent (Berleant et al., 2009). 

    We observed that APP A713T increases the Aβ42/Aβ40 ratio in plasma (Conidi et al., 2015). Studies in cell culture may elucidate the effects of the mutation on APP processing, and whether the presence of the nearby silent mutation affects this.

    For reasons that are currently unclear, human carriers of A713T present with either classic Alzheimer’s pathology or prominent CAA with significant vascular lesions. It would be interesting to determine the pattern of amyloid pathology in a mouse model and to explore potential modifiers of that pathology.

    References:

    . Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.

    . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.

    . A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.

    . AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.

    . The genetic code--more than just a table. Cell Biochem Biophys. 2009;55(2):107-16. Epub 2009 Jul 29 PubMed.

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References

Paper Citations

  1. . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
  2. . A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PubMed.
  3. . Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.
  4. . Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family. Neurology. 2015 Jun 2;84(22):2266-73. Epub 2015 May 6 PubMed.
  5. . AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions. J Alzheimers Dis. 2009;17(2):383-9. PubMed.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database (single mutation)
  2. Alzheimer Disease & Frontotemporal Dementia Mutation Database (double mutation)

Primary Papers

  1. . More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PubMed.
  2. . Familial Alzheimer disease associated with A713T mutation in APP. Neurosci Lett. 2004 Nov 11;370(2-3):241-3. PubMed.

Other mutations at this position

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