Mutations

PSEN1 E318G

Overview

Pathogenicity: Alzheimer's Disease : Risk Modifier
Clinical Phenotype: None
Reference Assembly: GRCh37 (105)
Position: Chr14:73673178 A>G
dbSNP ID: RS17125721
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 9

Findings

This variant was initially found in people with early onset Alzheimer's disease (e.g., Taddei et al., 2002; Albani et al., 2007); however, it did not segregate with disease. It was also identified in individuals with late-onset AD and in healthy controls (e.g., Mattila et al., 1998; Dermaut et al., 1999; Aldudo et al., 1998; Zekanowski et al., 2004; Helisalmi et al., 2000). Taken together, these findings indicate that the E318G variant is unlikely to cause AD; however, it may increase risk.

In a study of individuals of Spanish descent, this variant was detected in two of 176 individuals with AD and three of 139 controls (Jin et al., 2012). The cases with AD were described as having sporadic early onset AD, with onset at 56.5 and 65.5 years of age. Further clinical details were not reported. The presence of this variant in controls led the authors to classify the variant as not pathogenic.

The E318G variant was found in about 5 percent of families affected by familial late onset AD (30 out of 565 families). The variant is more frequently found in cases of familial late-onset AD than in cases of "sporadic" late-onset AD (Benitez et al., 2013). This mutation also turned up in a study that sequenced AD-associated genes in people with extreme biomarker levels of in their cerebrospinal fluid (Benitez et al., 2013; Sep 2013 news). Specifically, the E318G variant was associated with high levels of total tau and phospho-tau. In APOE ε4 carriers it was also associated with Aβ deposition and faster cognitive decline. Furthermore, at least two studies have found that APOE ε4 carriers who also carry the PSEN1 E318G variant were at greater risk of developing late-onset AD, than APOE ε4 carriers without the variant (Benitez et al., 2013; Nho et al., 2016); however, a study of 3420 individuals found no significant association of E318G and AD, regardless of APOE genotype (Hippen et al., 2016).

In a study of 72 AD cases and 58 controls, the E318G variant was detected in one individual with AD and in one control, the latter lacking significant AD neuropathology postmortem. Additional information regarding these two mutation carriers, including their ages, was not reported (Frigerio et al., 2015). Moreover, a study of two Brazilian cohorts, including 53 individuals with a familial history of AD and 120 with sporadic AD, concluded that the E318G variant increases AD risk, independently of APOE4 status (Abdala et al., 2017).

The PSEN1 E318G variant may increase the risk of dementia with Lewy bodies. In a cohort of 111 pathologically confirmed cases of this disease, 10 individuals carried the mutation, a frequency much higher than seen in controls (Geiger et al., 2016).

Neuropathology

At least one mutation carrier lacked AD neuropathology (Frigerio et al., 2015).

Biological Effect

Although one study reported increased tau and phospho-tau levels in the CSF of E318G carriers (Benitez et al., 2013), no changes in several CSF AD markers, including total tau and phospho-tau as well as Aβ42, were found in asymptomatic members of a large Italian family (Artuso et al., 2019). Plasma Aβ40 levels, however, were increased in the Italian carriers. In vitro experiments have also yielded mixed results. In HEK293 cells transfected with PSEN1 E318G, secretion of both Aβ40 and Aβ42 peptides was robustly increased compared to controls (Bialopiotrowicz et al., 2012). However, Aβ40 and Aβ42 production was reduced to undetectable levels in experiments using isolated proteins (Sun et al., 2017).

 

Last Updated: 22 Mar 2019

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References

News Citations

  1. Going to Biomarker Extremes to Find Rare Alzheimer’s Variants

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. . Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort. Alzheimers Res Ther. 2012 Aug 20;4(4):34. PubMed.
  9. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
  10. . Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease. BMC Med Genomics. 2016 Aug 12;9 Suppl 1:30. PubMed.
  11. . Presenilin E318G variant and Alzheimer's disease risk: the Cache County study. BMC Genomics. 2016 Jun 29;17 Suppl 3:438. PubMed.
  12. . Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil. Neurosci Lett. 2017 Jul 13;653:341-345. Epub 2017 May 26 PubMed.
  13. . Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis. 2016 Oct;94:55-62. Epub 2016 Jun 14 PubMed.
  14. . Asymptomatic Carriers of Presenilin-1 E318G Variant Show no Cerebrospinal Fluid Biochemical Signs Suggestive of Alzheimer's disease in a Family with Late-onset Dementia. Curr Alzheimer Res. 2019;16(1):1-7. PubMed.
  15. . Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes. J Alzheimers Dis. 2012 Jan 1;32(2):397-415. PubMed.
  16. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Other Citations

  1. Frigerio et al., 2015

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.
  6. . Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants. Mol Neurobiol. 2016 Sep 19; PubMed.
  7. . Atypical Huntington's disease with the clinical presentation of behavioural variant of frontotemporal dementia. J Neural Transm (Vienna). 2016 Dec;123(12):1423-1433. Epub 2016 Jun 10 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

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.

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