Mutations

APP E693del (Osaka)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275271_275273delAGA
Genomic Mutation Name (NT1): g.283967_283969delAGA
dbSNP ID:
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Deletion
Codon Change: GAA to ---

Findings

This deletion mutation was identified in two families from Japan (Tomiyama et al., 2008). The larger pedigree consisted of seven affected individuals over two generations. DNA was available from two affected family members and both were homozygous for the deletion mutation.

The proband of this kindred was a 62-year-old Japanese 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 atypical symptoms such as cerebellar ataxia or pyramidal signs, suggesting these may not be obligatory phenotypes of E693del.

The screen turned up two individuals who were heterozygous carriers of E693del. One individual had mild cognitive impairment at age 81 and the other was healthy at age 64. 

The authors note that because a homozygous deletion was found in a total of three affected individuals across two families, it is likely to be pathogenic in the homozygous state. Incomplete penetrance is also a formal possibility.

Neuropathology

Postmortem analysis was unavailable. A low amyloid signal was observed by PET amyloid imaging using PiB (Tomiyama et al., 2008).

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. 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 ratio. The mutant Aβ that is produced is more resistant to degradation by two major Aβ-degrading enzymes, neprilysin and insulin-degrading enzyme. Synthetic mutant Aβ showed unusual aggregation properties with 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 mice exhibit intraneuronal Aβ oligomers and memory impairment as early as 8 months of age (Umeda et al., 2012).

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References

Paper Citations

  1. . Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice. Life Sci. 2012 Jan 17; PubMed.
  2. . A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann Neurol. 2008 Mar;63(3):377-87. 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

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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