Mutations

PSEN1 E280G

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Genomic Mutation Name (MET1): g.50024A>G
Genomic Mutation Name (NT1): g.66630A>G
dbSNP ID: rs63750231
Coding/Non-Coding: Coding
Genomic Region: Exon 8
Mutation Type: Point, Missense
Codon Change: GAA to GGA

Findings

This mutation has been identified in several families from Europe and the United Kingdom, including France and Ireland. It was first reported in two U.K. families in association with the cloning of the PSEN1 gene in 1995 (Clark et al., 1995). The families, identified as F168 and F183, had five and two affected members, respectively, over three generations. The average age of onset was reported as 41 and 43 years. The diagnosis of AD was confirmed in one member in the F168 family (Clark et al., 1995; Hutton et al., 1996).

An Irish family with this mutation has been documented with nine affected family members over three generations. The typical clinical phenotype in this family was described as dementia with myoclonus with onset early in the fifth decade. Some patients (two out of nine) developed symptoms of spastic paraparesis (O’Riordan et al., 2002).

Two French families have also been described. One, called Alz 150, reportedly consisted of four individuals affected by dementia starting between 43 and 47 years old. Additional clinical details were not reported (Raux et al., 2005). Another French family was described as containing three affected family members. Onset of dementia in this family occurred between the ages of 40 and 48 years. Early gait disturbance was noted in one affected family member. Genetic analysis was only available for one individual, so segregation with disease could not be formally assessed (Dumanchin et al., 2006).

An additional family was reported with five affected individuals over two generations. The proband presented with memory difficulties and weakness in both legs beginning at age 53. The mutation, reported as E280Q, was detected in the proband, but segregation with disease could not be formally assessed due to lack of DNA from family members. No mutations in APP or PSEN2 were found (Rogaeva et al., 2003).

Neuropathology

Brain biopsy in one individual from the Irish family showed numerous large, diffuse, non-cored, cotton-wool plaques. Prominent amyloid angiopathy was also noted, affecting cortical and meningeal vessels. This individual presented at age 40 with cognitive impairment and subsequently developed gait difficulties and spastic–ataxic quadriparesis. In at least two affected family members, white-matter abnormalities were seen on cranial MRI (O’Riordan et al., 2002). Similarly, abundant cotton-wool plaques were detected in a presumably unrelated individual who also had vascular amyloid deposits and degeneration of the corticospinal tracts (Rogaeva et al., 2003). Neuropathological examination of a member of a French kindred also found cotton-wool plaques as well as mild degeneration of the corticospinal tract (Dumanchin et al., 2006).

Biological Effect

When expressed in HEK-293 cells, the mutant PSEN1 was associated with a significant increase in Aβ42 and the Aβ42/Aβ40 ratio in the conditioned media (Dumanchin et al., 2006).

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References

Paper Citations

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  3. . Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities. Neurology. 2002 Oct 8;59(7):1108-10. PubMed.
  4. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
  5. . Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques. Hum Mutat. 2006 Oct;27(10):1063. PubMed.
  6. . PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology. 2003 Oct 14;61(7):1005-7. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
  2. . Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities. Neurology. 2002 Oct 8;59(7):1108-10. PubMed.

Other mutations at this position

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