Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640294 A>G
dbSNP ID: NA
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 5

Findings

This mutation is associated with early onset Alzheimer's disease in a Spanish kindred (Lladó et al., 2010; Gómez-Tortosa et al., 2010). This family was noted to have a particularly homogeneous age at onset (around 39 to 40 years), epileptic activity, and very rapid cognitive and functional deterioration.

The proband began to experience memory loss and progressive cognitive decline in his 30s. As the disease progressed, he developed seizures and difficulties with gait. He died at the age of 44. His father, paternal uncle, and sister were also affected. The father had developed behavioral disturbances and memory deficits around age 39 and died at age 42. He had generalized seizures. His homozygous twin brother also developed symptoms in his late 30s and died at age 42. The proband’s sister began having recurrent generalized seizures at age 39. Memory deficits began simultaneously and progressed to substantial cognitive deterioration within two years. The mutation was reported to segregate with disease in this family (Gómez-Tortosa et al., 2010).

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Neuropathological examination of the proband’s brain revealed frequent amyloid plaques and neurofibrillary tangles along with severe amyloid angiopathy (Lladó et al., 2010).

Biological Effect

This mutant appears to reduce γ-processivity resulting in longer Aβ peptides and an increase in the Aβ42/Aβ40 ratio. In membrane samples from a patient brain incubated with tagged APP-C99 substrate, production rates of Aβ38 and Aβ40 were decreased compared with control samples (Szaruga et al., 2015). The authors noted that the mutation likely impairs the fourth γ-secretase cleavage in the Aβ production line(s) that sequentially digest Aβ into shorter peptides, as revealed by a decrease in the Aβ38/Aβ42 (product/substrate) ratio. Similarly, in mouse embryonic fibroblasts transfected with PSEN1 E120G, the Aβ38/Aβ42 ratio was approximately 10-fold reduced. The authors also found that APP intracellular domain production was approximately 30 percent of wild-type levels.

Subsequent studies have confirmed and extended these results (Liu et al., 2021, Sarroca et al., 2016). In particular, analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed an increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios (Liu et al., 2021). Total secreted Aβ levels were reduced. Interestingly, the authors of this study also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations, including E120G.

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 (Gómez-Tortosa et al., 2010, 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-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

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.

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

Paper Citations

Lladó A, Sánchez-Valle R, Rey MJ, Mercadal P, Almenar C, López-Villegas D, Fortea J, Molinuevo JL. [New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. Neurologia. 2010 Jan-Feb;25(1):13-6. PubMed.
Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Muñoz DG, Jiménez-Huete A, Rábano A, Sainz MJ, Guerrero R, Gobernado I, Pérez-Pérez J, Jiménez-Escrig A. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. PubMed.
Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, Ryan NS, Lashley T, Fox NC, Murayama S, Gijsen H, De Strooper B, Chávez-Gutiérrez L. Qualitative changes in human γ-secretase underlie familial Alzheimer's disease. J Exp Med. 2015 Nov 16;212(12):2003-13. Epub 2015 Oct 19 PubMed.
Liu L, Lauro BM, Wolfe MS, Selkoe DJ. Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021;296:100393. Epub 2021 Feb 8 PubMed.
Sarroca S, Molina-Martínez P, Aresté C, Etzrodt M, García de Frutos P, Gasa R, Antonell A, Molinuevo JL, Sánchez-Valle R, Saura CA, Lladó A, Sanfeliu C. Preservation of cell-survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype. Neurobiol Aging. 2016 Oct;46:169-79. Epub 2016 Jul 15 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 E120G

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