Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640392 C>G
dbSNP ID: rs63751441
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to GTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first identified in two members of a French family with five individuals diagnosed with probable AD, spanning three generations (Raux et al., 2000). Age of onset ranged between 34 and 38 years of age. Symptoms were typical of AD, including early memory loss, spatial disorientation, and progressive deterioration of praxis and language. The mutation was absent from 50 unrelated Caucasian controls.

The mutation was also found in English and Peruvian kindreds, which similarly developed AD symptoms very early, starting in the mid-30s. The English family included three affected members, two with confirmed mutations, spanning three generations (Janssen et al. 2001, Ryan et al., 2016). The Peruvian family included eight affected members, with four confirmed mutation carriers, across two generations (Cornejo-Olivas et al., 2014). Memory loss and language impairment were observed, as well as myoclonus, seizures, and spasticity. Mean age at onset was 37 years. The mutation was absent from one unaffected member in this family. Based on genotypic analyses, the Peruvian family’s mutation may have an Amerindian or African origin.

Although affected individuals in all families were diagnosed with probable AD, there was symptom variability. For example, the English family had one member with myoclonus and none with seizures or spasticity, whereas all three symptoms were reported in the Peruvian family. Seizures were also reported in two of three French mutation carriers in a subsequent study (Zarea et al. 2016).

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

Neuropathology

In one case, neuropathology was consistent with severe AD, including abundant neurofibrillary tangles, neuritic plaques, and neuropil threads in the hippocampus and cerebral cortex (Janssen et al. 2001). Extensive deposition of Aβ was seen in both the cerebral parenchyma and blood vessels. Moreover, occasional Lewy bodies were found in the trans-entorhinal, cingulate, insular, and parietal cortices.

Biological Effect

In conditioned media of human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant, the Aβ42/Aβ40 ratio was elevated compared with that of control cells, and the Aβ37/Aβ42 ratio was decreased, suggesting a damaging effect (Liu et al., 2022, Apr 2022 news). Of note, the Aβ37/Aβ42 ratio outperformed Aβ42/Aβ40 at distinguishing control versus AD samples. Consistently, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate also showed elevation of Aβ42/Aβ40 (Sun et al., 2017). However, in the cell-based study, Aβ42 and Aβ43 production were elevated and Aβ40 was similar to controls, while in the in vitro experiments, both Aβ42 and Aβ40 levels were decreased (Aβ43 levels were not measured).

The mutation affects an amino acid conserved in PSEN2 and in dps, the Drosophila melanogaster homolog of PSEN1. 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-S

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

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. L153V: The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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.

PP1-M

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. L153V: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 21 Aug 2022

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References

News Citations

Paper Citations

Raux G, Gantier R, Martin C, Pothin Y, Brice A, Frebourg T, Campion D. A novel presenilin 1 missense mutation (L153V) segregating with early-onset autosomal dominant Alzheimer's disease. Hum Mutat. 2000 Jul;16(1):95. PubMed.
Janssen JC, Lantos PL, Fox NC, Harvey RJ, Beck J, Dickinson A, Campbell TA, Collinge J, Hanger DP, Cipolotti L, Stevens JM, Rossor MN. Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation. Arch Neurol. 2001 Jun;58(6):953-8. PubMed.
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
Cornejo-Olivas MR, Yu CE, Mazzetti P, Mata IF, Meza M, Lindo-Samanamud S, Leverenz JB, Bird TD. Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease. Neurosci Lett. 2014 Mar 20;563:140-3. Epub 2014 Feb 2 PubMed.
Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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.
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 L153V

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