Mutations

APP E693G (Arctic)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.275270A>G
Genomic Mutation Name (NT1): g.283966A>G
dbSNP ID: rs63751039
Coding/Non-Coding: Coding
Genomic Region: Exon 17
Mutation Type: Point, Missense
Codon Change: GAA to GGA
Research Models: 5

Findings

This mutation was identified in a four-generation family from northern Sweden. Affected individuals presented with clinical features of early-onset Alzheimer's disease with a mean age of onset of 57 ± 2.9 years and insidious cognitive decline (Nilsberth et al., 2001). The mutation was also reported in an individual of Swedish origin living in the United States who is thought to be a member of the same kindred (Kamino et al., 1992). Plasma levels of both Aβ42 and Aβ40 were lower in mutation carriers than in healthy family members (Nilsberth et al., 2001).

Neuropathology

No signs of strokes or vascular lesions were found by brain imaging (Nilsberth et al., 2001). Neuropathology is available for only one mutation carrier and showed neuritic plaques and neurofibrillary tangles consistent with a diagnosis of AD (Kamino et al., 1992). Cortical PiB retention was very low in two Arctic mutation carriers compared with both non-carrier siblings and two individuals with other pathogenic mutations (APP Swedish and PSEN1 H163Y). Cerebral glucose metabolism was abnormal in all mutation carriers, as were CSF levels of Aβ(1-42), total tau, and phosphorylated tau (Schöll et al., 2012).

Biological Effect

Arctic Aβ40 displays an increased propensity to form protofibrils compared with wild-type Aβ40 and at a faster rate (Nilsberth et al., 2001). In addition, the Arctic mutation was one of several pathogenic APP mutations found to confer resistence to neprilysin-catalyzed proteolysis of Aβ40 (Tsubuki et al., 2003).

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References

Mutations Citations

  1. APP KM670/671NL (Swedish)
  2. PSEN1 H163Y

Paper Citations

  1. . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
  2. . Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992 Nov;51(5):998-1014. PubMed.
  3. . Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology. 2012 Jul 17;79(3):229-36. PubMed.
  4. . Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet. 2003 Jun 7;361(9373):1957-8. PubMed.

Further Reading

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Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992 Nov;51(5):998-1014. PubMed.
  2. . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.

Other mutations at this position

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