Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217170 C>G
Position: (GRCh37/hg19):Chr14:73683878 C>G
dbSNP ID: rs63751416
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 11

Findings

This mutation has been reported in multiple individuals and families worldwide. It was first described in conjunction with the cloning of the PSEN1 gene (Rogaev et al., 1995). In this original study, it was found in members of an Italian pedigree affected by a familial form of early onset Alzheimer's disease (AD). Further details about this kindred were not reported.

The L392V mutation was also found in an exceptionally large French kindred, FAD RO1, with at least 36 family members affected by early onset Alzheimer’s (Campion et al., 1995; Campion et al., 1995; Campion et al., 1999). The six-generation pedigree indicates the disease is an autosomal-dominant trait, and genetic analysis confirmed segregation with disease. At least 12 family members met NINCDS-ADRDA criteria for probable AD, and two had autopsy-confirmed AD. In this family, onset ranged from 39 to 52 years of age, with a mean onset of 46 ± 3.5 years and mean age at death of 52.6 ± 5.7 years. Disease in this family was characterized by insidious loss of memory and personality changes, followed by parkinsonism symptoms, including limb rigidity, stooped posture, and bradykinesia. Hallucinations occurred in some affected family members. Myoclonus was frequent, and seizures were an invariable feature of late-stage disease.

Another study found two kindreds carrying the L392V mutation (Raux et al., 2005). The ALZ 147 family had six members affected by early onset familial AD. Onset ranged from 41 to 48 years of age. The ALZ 154 family included five members affected by AD, with onset ranging from 39 to 47 years of age. Further clinical details were not reported.

This mutation was also detected in the proband of a Japanese kindred affected by early onset AD (Ikeuchi et al., 2008). The reported pedigree shows eight affected individuals over three generations. Segregation could not be determined. The proband developed onset at age 39.

In a study of individuals of Spanish descent, this mutation was detected in one out of 176 cases with Alzheimer's disease (Jin et al., 2012). The mutation carrier was described as having familial early onset Alzheimer's, with symptoms starting at age 42.5. Further clinical details were not reported.

The variant was also reported in a woman diagnosed with Alzheimer’s disease from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias from 1795 patients were sequenced (Jiao et al., 2021). Her age at onset was 46 years and her APOE genotype was APOE E3/E3. She had a family history of AD and suffered from memory impairment, as well as from mental and behavioral changes. 

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

Neuropathology

At least two mutation carriers met CERAD criteria for definite AD. Postmortem findings showed cortical atrophy, especially in the frontal and temporal lobes, with abundant plaques and neurofibrillary tangles throughout the neocortex and hippocampus. Mild amyloid angiopathy was observed. Lewy bodies were not observed (Campion et al., 1995).

Biological Effect

When expressed in HEK293, this mutation impaired the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage of APP (Ikeuchi et al., 2008; Li et al., 2016). In particular, this mutation was reported to increase the Aβ48-39 production line, resulting in increased secreted Aβ42, and an increased Aβ42/Aβ40 ratio. In an in vitro assay using purified proteins to test the mutant’s ability to cleave the APP-C99 substrate, however, the mutant generated less Aβ40 than wildtype PSEN1, but similar amounts of Aβ42. The resulting Aβ42/Aβ40 ratio was increased approximately two-fold (Sun et al., 2017).

Although no effect on the proteolytic processing of PSEN1 was detected in transiently transfected PC12 and C6 glioma cells (Murayama et al., 1997), a subsequent study in HEK293 cells stably expressing mutant PSEN1, revealed the N-terminal fragment (NTF) of presenilin-1 was decreased, suggesting impaired endoproteolysis. Moreover, levels of the intracellular domain of Notch protein were decreased, suggesting reduced Notch cleavage by γ-secretase (Ikeuchi et al., 2008). The L392V mutation has also been reported to decrease PSEN1’s affinity for glycogen synthase kinase-3 β, which phosphorylates tau (Gantier et al., 2000).

Disruption of PSEN1 structure may underlie at least some of these effects. As assessed by circular dichroism, the α-helical content of mutant PSEN1 was reduced compared to that of wild-type PSEN1 when the proteins were immersed in phospholipids, an environment that mimics the plasma membrane (Gantier et al., 1999).

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.

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References

Paper Citations

1. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PubMed.
2. Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
3. Campion D, Brice A, Hannequin D, Tardieu S, Dubois B, Calenda A, Brun E, Penet C, Tayot J, Martinez M. A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization. Neurology. 1995 Jan;45(1):80-5. PubMed.
4. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
5. 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.
6. Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, Tsuchiya M, Imamura T, Ishizu H, Aoki K, Ishikawa A, Onodera O, Kuwano R, Nishizawa M. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
7. Jin SC, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C, Goate A, Ibero-American Alzheimer Disease Genetics Group Researchers, Cruchaga C. 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.
8. Jiao B, Liu H, Guo L, Xiao X, Liao X, Zhou Y, Weng L, Zhou L, Wang X, Jiang Y, Yang Q, Zhu Y, Zhou L, Zhang W, Wang J, Yan X, Li J, Tang B, Shen L. The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
9. Li N, Liu K, Qiu Y, Ren Z, Dai R, Deng Y, Qing H. Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. Epub 2016 Mar 11 PubMed.
10. 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.
11. Murayama O, Honda T, Mercken M, Murayama M, Yasutake K, Nihonmatsu N, Nakazato Y, Michel G, Song S, Sato K, Takahashi H, Takashima A. Different effects of Alzheimer-associated mutations of presenilin 1 on its processing. Neurosci Lett. 1997 Jun 20;229(1):61-4. PubMed.
12. Gantier R, Gilbert D, Dumanchin C, Campion D, Davoust D, Toma F, Frébourg T. The pathogenic L392V mutation of presenilin 1 decreases the affinity to glycogen synthase kinase-3 beta. Neurosci Lett. 2000 Apr 14;283(3):217-20. PubMed.
13. Gantier R, Dumanchin C, Campion D, Loutelier C, Lange C, Gagnon J, Davoust D, Frébourg T, Toma F. The L392V mutation of presenilin 1 associated with autosomal dominant early-onset Alzheimer's disease alters the secondary structure of the hydrophilic loop. Neuroreport. 1999 Sep 29;10(14):3071-4. PubMed.
14. 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

Learn More

1. Japanese Familial Alzheimer's Disease Database