Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192798 C>G
Position: (GRCh37/hg19):Chr14:73659506 C>G
dbSNP ID: rs63751130
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 7

Findings

This mutation has been reported in two families from the United Kingdom and Mexico. The UK kindred, Family 267, included six affected individuals over three generations. The mean age at onset was reported as 47, with a range of 44-50 years. The diagnosis of Alzheimer's disease was confirmed postmortem in at least one case. The mutation was present in two affected family members and absent in 100 unrelated control individuals (Janssen et al., 2003).

The L235V mutation was also reported in a Mexican family with familial dementia starting around age 48. Further clinical details were not described, although 11 asymptomatic female family members participated in a depression screen. Mutation carriers had a higher incidence of depression than non-carriers, even when they were naïve to their mutation status, supporting the hypothesis that depression is an early clinical feature related to AD pathology (Ringman et al., 2004).

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

Neuropathology

Neuropathology consistent with a diagnosis of AD was found in at least one case (Janssen et al., 2003).

Biological Effect

Two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, modestly decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. Although the Aβ42/Aβ40 ratio was increased in cells, it was similar to controls in an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate (Sun et al., 2017). This study also showed a reduction in both Aβ40 and Aβ42 levels, which was also observed in one of the cell assays (Liu et al., 2022).

In addition, the association of L235V with depression led researchers to study its effect on monoamine-oxidase-A (MAO-A), an enzyme that degrades serotonin and noradrenaline. Expression of mutant PSEN1 in a murine hippocampal cell line resulted in higher MAO-A activity compared with cells expressing wild-type PSEN1, suggesting that L235V may predispose to depression by affecting neurotransmitter metabolism. In addition, co-immunoprecipitation experiments suggested a possible direct interaction of PSEN1 with MAO-A (Pennington et al., 2011).

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 : Likely Pathogenic

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

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Paper Citations

1. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
2. Ringman JM, Diaz-Olavarrieta C, Rodriguez Y, Chavez M, Paz F, Murrell J, Macias MA, Hill M, Kawas C. Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their non-mutation carrying kin. J Neurol Neurosurg Psychiatry. 2004 Mar;75(3):500-2. PubMed.
3. Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
4. 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.
5. 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.
6. Pennington PR, Wei Z, Rui L, Doig JA, Graham B, Kuski K, Gabriel GG, Mousseau DD. Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro. J Neural Transm. 2011 Jul;118(7):987-95. PubMed.
7. 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.

External Citations

1. gnomAD v2.1.1

Further Reading