Mutations

APP E693del (Osaka)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1):
Genomic Mutation Name (NT1):
dbSNP ID:
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Deletion
Codon Change: GAA to ---
Research Models: 1

Findings

This in-frame microdeletion has been identified in at least three families from Japan. It appears to be recessive and pathogenic only in the homozygous state. However, it is also possible that the absence of disease in the relatively small number of known heterozygous carriers is due to incomplete penetrance.

The largest pedigree consists of seven affected individuals over two generations (Tomiyama et al., 2008). DNA was available from two affected family members and both were homozygous for the deletion. The proband of this kindred was a 62-year-old woman who developed memory impairment at age 55. She later developed cerebellar ataxia, gait disturbance, and pyramidal signs, such as an abnormal Babinski reflex. She was diagnosed with AD at age 59 and had severe dementia by age 62. Her sister developed AD at age 59. DNA was not available from a third affected sister. Two heterozygous sisters were unaffected at age 56 and 65. No mutations were found in PSEN1 or PSEN2.

The authors subsequently screened 5,310 Japanese people with and without AD and found another homozygous individual who had developed AD at age 36. Unlike the proband in the previously described kindred, this individual did not have cerebellar ataxia or pyramidal signs, suggesting these may not be obligatory phenotypes of E693del. The screen also turned up two individuals who were heterozygous carriers. One individual had mild cognitive impairment at age 81 and the other was cognitively healthy at age 64. 

More recently, three siblings from an isolated island in Japan were found to be homozygous for this microdeletion (Kutoka et al., 2015). Their parents were first-degree cousins and cognitively healthy. The proband developed short-term memory impairment at age 35. She was diagnosed with AD at age 42 based on progressive cognitive impairment and spatial disorientation. Later she developed difficulty walking due to spastic paraparesis in her lower limbs. Her brother and sister developed similar symptoms but had a slightly milder clinical course. They developed symptoms at age 59 and 44 respectively, with spastic paraparesis setting in at ages 66 and 58. All three affected siblings ultimately became mute. An unaffected sibling was found to be a heterozygous carrier of the deletion.

Neuropathology

Postmortem analysis is not available for affected individuals carrying the E693Δ mutation; however, imaging studies have shown an unusually low amyloid signal by PiB-PET, and only mild atrophy considering the degree of cognitive impairment (Tomiyama et al., 2008; Shimada et al., 2011). In a putative unrelated kindred, a similar absence of amyloid deposition was revealed by PiB-PET, despite severe dementia. MRI showed generalized brain atrophy and FDG-PET showed severe impairment of glucose uptake. Analysis of cerebral spinal fluid showed low levels of overall Aβ, but elevated levels of high molecular weight species, presumably Aβ oligomers (Kutoka et al., 2015).

Biological Effect

This mutation involves the deletion of the entire 693 codon, which is located within the Aβ sequence of APP. The Aβ peptides produced from this mutant APP lack glutamate at position 22, and are therefore called E22delta or E22Δ. Compared with cells transfected with wild-type APP, HEK cells transfected with mutant APP produce lower levels of Aβ42 and Aβ40 with no change in the peptide ratio. The mutant Aβ that is produced is more resistant to degradation by two major Aβ-degrading enzymes, neprilysin and insulin-degrading enzyme.

In vitro, synthetic E22Δ Aβ showed unusual aggregation properties: notably enhanced oligomerization but no fibrillization. It also inhibited hippocampal LTP more potently than wild-type Aβ (Tomiyama et al., 2008).

Research Models

A transgenic mouse model containing APP with the E693del mutation has been developed. APP(OSK)-Tg mice exhibit intraneuronal Aβ oligomers and memory impairment as early as 8 months of age (Tomiyama et al., 2010; Umeda et al., 2012).

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References

Research Models Citations

  1. APP E693Δ-Tg (Osaka transgenic)

Paper Citations

  1. . A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci. 2010 Apr 7;30(14):4845-56. PubMed.
  2. . Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice. Life Sci. 2012 Jan 17; PubMed.
  3. . A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann Neurol. 2008 Mar;63(3):377-87. PubMed.
  4. . A second pedigree with amyloid-less familial Alzheimer's disease harboring an identical mutation in the amyloid precursor protein gene (E693delta). Intern Med. 2015;54(2):205-8. Epub 2015 Jan 15 PubMed.
  5. . Clinical course of patients with familial early-onset Alzheimer's disease potentially lacking senile plaques bearing the E693Δ mutation in amyloid precursor protein. Dement Geriatr Cogn Disord. 2011;32(1):45-54. PubMed.

Further Reading

Papers

  1. . Solid-state NMR sequential assignment of Osaka-mutant amyloid-beta (Aβ1-40 E22Δ) fibrils. Biomol NMR Assign. 2014 Jan 7; PubMed.
  2. . The Osaka FAD mutation E22Δ leads to the formation of a previously unknown type of amyloid β fibrils and modulates Aβ neurotoxicity. J Mol Biol. 2011 May 13;408(4):780-91. PubMed.
  3. . Alzheimer's disease amyloid β-protein mutations and deletions that define neuronal binding/internalization as early stage nonfibrillar/fibrillar aggregates and late stage fibrils. Biochemistry. 2012 May 15;51(19):3993-4003. PubMed.
  4. . Proteomic analysis of the brain tissues from a transgenic mouse model of amyloid β oligomers. Neurochem Int. 2012 May 23;61(3):347-355. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann Neurol. 2008 Mar;63(3):377-87. PubMed.

Other mutations at this position

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