Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198100 A>G
Position: (GRCh37/hg19):Chr14:73664808 A>G
dbSNP ID: rs63750231
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation has been identified in several families with Alzheimer's disease (AD) 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. Absence of the mutation in unaffected members and formal linkage analysis (LOD score greater than 2) indicated co-segregation with disease (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).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

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). An increase in the Aβ42/Aβ40 ratio was also reported in a subsequent study using an in vitro assay to test the ability of this mutant to cleave the APP-C99 substrate (Sun et al., 2017). In this case, however, Aβ42, and especially Aβ40, production were reduced compared to wild-type PSEN1. In addition, the mutant caused incomplete endoproteolytic processing of PSEN1.

As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, E280 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for γ-secretase cleavage (Zhou et al., 2019; Jan 2019 news). The carboxylate side chain of E280 makes a bifurcated H-bond to the hydroxyl groups of Y154 and Y159, both from transmembrane domain 2 of PSEN1. These interactions are buttressed by two additional H-bonds from R278 to E280 and Y159.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. E280G: Functional observations are mixed, but they consistently showed a damaging effect.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. E280G: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. E280G: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. E280G: Cosegregation demonstrated in >1 family.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 22 Feb 2022

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References

News Citations

Paper Citations

Alzheimer's Disease Collaborative Group. 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.
Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, Prihar G, Talbot C, Phillips H, Wright K, Baker M, Lendon C, Duff K, Martinez A, Houlden H, Nichols A, Karran E, Roberts G, Roques P, Rossor M, Venter JC, Adams MD, Cline RT, Phillips CA, Goate A. Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
O'Riordan S, McMonagle P, Janssen JC, Fox NC, Farrell M, Collinge J, Rossor MN, Hutchinson M. Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities. Neurology. 2002 Oct 8;59(7):1108-10. PubMed.
Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. 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.
Dumanchin C, Tournier I, Martin C, Didic M, Belliard S, Carlander B, Rouhart F, Duyckaerts C, Pellissier JF, Latouche JB, Hannequin D, Frebourg T, Tosi M, Campion D. 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.
Rogaeva E, Bergeron C, Sato C, Moliaka I, Kawarai T, Toulina A, Song YQ, Kolesnikova T, Orlacchio A, Bernardi G, St George-Hyslop PH. PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology. 2003 Oct 14;61(7):1005-7. PubMed.
Sun L, Zhou R, Yang G, Shi Y. 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.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Mutations

PSEN1 E280G

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