Mutations

PSEN1 E318G

Overview

Pathogenicity: Alzheimer's Disease : Not Pathogenic
Clinical Phenotype: None
Genomic Mutation Name (MET1): g.58389A>G
Genomic Mutation Name (NT1): g.75001A>G
dbSNP ID: RS17125721
Coding/Non-Coding: Coding
Genomic Region: Exon 9
Mutation Type: Point, Missense
Codon Change: GAA to GGA

Findings

This variant was initially found in patients with early-onset Alzheimer's disease (e.g. Taddei et al., 2002; Albani et al., 2007), but was also found in healthy controls and individuals with late-onset AD (Mattila et al., 1998; Dermaut et al., 1999; Aldudo et al., 1998; Zekanowski et al., 2004; Helisalmi et al., 2000). The lack of segregation with disease argues against this variant being causative for familial early-onset AD, but it may be a risk factor for late-onset AD.

In 2013, this mutation turned up in a study which sequenced AD-associated genes in individuals with extreme levels of Aβ and tau in their cerebral spinal fluid. Specifically, this mutation was associated with elevated levels of total tau and phosphorylated tau. Notably, in APOE ε4 allele carriers it was also associated with Aβ deposition and  and faster cognitive decline. Furthermore, in a large case-control series of over 5000 individuals, it was found that people who carry both an APOE ε4 allele and the PSEN1 E318G variant were at elevated risk of developing AD, with a risk similar to carrying two APOE ε4 alleles, and double the risk of APOE ε4 carriers who do not carry E318G. The mechanism underlying the interaction of these two genetic risk factors is currently unknown.

The same study found that the E318G variant is present in 5.3 percent of the families from a large clinical series of late-onset AD families (30 out of 565 families) and exhibited a higher frequency in familial late-onset AD than in sporadic late-onset AD (Benitez et al., 2013).

Neuropathology

Unknown.

Biological Effect

Unknown.

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References

Paper Citations

  1. . Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population. Mol Psychiatry. 2002;7(7):776-81. PubMed.
  2. . Presenilin-1 mutation E318G and familial Alzheimer's disease in the Italian population. Neurobiol Aging. 2007 Nov;28(11):1682-8. PubMed.
  3. . The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease. Ann Neurol. 1998 Dec;44(6):965-7. PubMed.
  4. . The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease. Am J Hum Genet. 1999 Jan;64(1):290-2. PubMed.
  5. . Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol. 1998 Dec;44(6):985-6. PubMed.
  6. . The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort. Neurosci Lett. 2004 Mar 11;357(3):167-70. PubMed.
  7. . Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease?. Neurosci Lett. 2000 Jan 7;278(1-2):65-8. PubMed.
  8. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.

Further Reading

Papers

  1. . Presenilin 1 Glu318Gly polymorphism: interpret with caution. Arch Neurol. 2005 Oct;62(10):1624-7. PubMed.
  2. . 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.
  3. . Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394V. Alzheimer Dis Assoc Disord. 2008 Apr-Jun;22(2):184-7. PubMed.
  4. . Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol. 2008 Apr;255(4):604-6. Epub 2008 Mar 25 PubMed.
  5. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Ann Neurol. 1996 Aug;40(2):265-6. PubMed.
  2. . Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
  3. . Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol. 1998 Dec;44(6):985-6. PubMed.