Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198117 C>G
Position: (GRCh37/hg19):Chr14:73664825 C>G
dbSNP ID: rs63751235
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8
Research Models: 15

Findings

The L286V mutation was first identified in a German kindred in conjunction with the cloning of the PSEN1 gene in 1995 (Sherrington et al., 1995). The family, known as FAD2, was described previously to include 21 individuals affected by Alzheimer's disease, three with an autopsy-confirmed diagnosis. Six affected carriers and multiple unaffected non-carriers indicated segregation of the mutation with disease. Dementia was often accompanied by extrapyramidal features and myoclonus. Ancestors were traced through seven generations and the inheritance pattern was observed to be consistent with autosomal-dominant transmission (Frommelt et al., 1991).

More than a decade later, this mutation was reported in a Japanese individual with a family history of early onset dementia (Ikeuchi et al., 2008). The proband, P2712, experienced symptom onset at age 47. His pedigree included five affected individuals over three generations, all of whom displayed progressive memory impairment consistent with a clinical diagnosis of AD.

Since then, L286V has been identified in other individuals of Asian ancestry. A screen of 148 Chinese individuals diagnosed with familial AD, for example, identified a female carrier with age at onset of 55 years (Gao et al., 2019). The woman suffered from memory impairment and disorientation. Of note, she was homozygous for the APOE4 AD risk factor. Her father and a brother, both deceased, were also affected. The variant was also found in two Han Chinese individuals with family histories of dementia. Ages at onset were 43 (Lin et al., 2020) and 50 (Mao et al., 2021). The latter had an APOE2/E3 genotype.

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

Neuropathology

Neuropathology was consistent with AD in at least three affected members of the FAD2 pedigree (Frommelt et al., 1991).

Biological Effect

Multiple studies have shown that L286V alters APP processing, increasing the Aβ42/Aβ total ratio in cultured cells (Citron et al., 1997; Murayama et al., 1999; Kulic et al., 2000) and in an assay with isolated proteins (Sun et al., 2017). In one study, using co-cultures of neurons and astrocytes derived from patient induced pluripotent stem cells (iPSCs), the Aβ42/Aβ40 ratio was similar to that of wildtype cells, but both Aβ40 and Aβ42 were elevated (Elsworthy et al., 2021). Also, this variant appears ti increase levels of the toxic peptide Aβ43 (Kakuda et al., 2021), and reduce Aβ43→Aβ40 cleavage, as noted in a preprint (Devkota et al., 2023).

Although an early study found no effect on ε-cleavage in cells over-expressing γ-secretase components (Quintero-Monzon et al., 2011), more recent studies with purified enzyme complexes indicate the substitution reduces this activity by 30 to 50 percent, without appreciably shifting cleavage site preference (Do et al., 2023; Devkota et al., 2023).

Experiments using iPSC-derived astrocytes and neurons also revealed a decrease in the non-amyloidogenic processing of APP, including a decreased ratio of sAβPP-α to sAβPP-β, decreased expression of ADAM10, an enzyme involved in the non-amyloidogenic processing of APP, as well as reduced sAβPP-α levels (Elsworthy et al., 2021).

A study using biochemical assays and molecular dynamics simulations suggested that L286V is able to adopt an active conformation, but it is substantially less accessible and flexible than that of wildtype PSEN1 (Do et al., 2023). Moreover, this alteration may result in a stalled, membrane-anchored APP/ γ-secretase complex which, as reported in a preprint, could be synaptotoxic (Devkota et al., 2023; Nov 2023 news).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicated that, in wild-type PSEN1, L286 is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Also, L286 has been implicated in the formation of an internal docking site that stabilizes substrate binding (Chen and Zacharias, 2022).

Other effects beyond APP processing have also been reported. For example, L286V has been shown to disrupt intracellular calcium dynamics (see Dec 2006 news; Landman et al., 2006; Oh et al., 2012; Yang et al., 2019; Hori et al., 2023), as well as alter the cellular redox status, elevating markers of protein carbonylation and lipid peroxidation (Elsworthy et al., 2021). The mutation does not appear to affect Notch endoproteolysis (Kulic et al., 2000; Ikeuchi et al., 2008).

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 (Gao et al., 2019; Lin et al., 2020; 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. L286V: The variant was reported in 3 or more unrelated patients with the same phenotype, and is 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. L286V: 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. L286V: At least one family with >=3 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)

Research Models

This pathogenic mutation is one of five introduced into the popular 5xFAD model of AD. The model also contains the PSEN1 mutation M146L (A>C) and three mutations in APP (Swedish, Florida, and London). In addition, IPSCs have been generated from a female Caucasian AD patient with disease onset at age 39 (Axol Bioscience, accessed on 2023).

Last Updated: 22 Dec 2023

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References

Mutations Citations

News Citations

Paper Citations

Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
Frommelt P, Schnabel R, Kühne W, Nee LE, Polinsky RJ. Familial Alzheimer disease: a large, multigeneration German kindred. Alzheimer Dis Assoc Disord. 1991;5(1):36-43. PubMed.
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.
Gao Y, Ren RJ, Zhong ZL, Dammer E, Zhao QH, Shan S, Zhou Z, Li X, Zhang YQ, Cui HL, Hu YB, Chen SD, Chen JJ, Guo QH, Wang G. Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
Lin YS, Cheng CY, Liao YC, Hong CJ, Fuh JL. Mutational analysis in familial Alzheimer's disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile. Sci Rep. 2020 Nov 13;10(1):19769. PubMed.
Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
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Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
Kulic L, Walter J, Multhaup G, Teplow DB, Baumeister R, Romig H, Capell A, Steiner H, Haass C. Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5913-8. 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.
Elsworthy RJ, King MC, Grainger A, Fisher E, Crowe JA, Alqattan S, Ludlam A, Hill DE, Aldred S. Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation. Mol Cell Neurosci. 2021 Jul;114:103631. Epub 2021 May 20 PubMed.
Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
Quintero-Monzon O, Martin MM, Fernandez MA, Cappello CA, Krzysiak AJ, Osenkowski P, Wolfe MS. Dissociation between the processivity and total activity of γ-secretase: implications for the mechanism of Alzheimer's disease-causing presenilin mutations. Biochemistry. 2011 Oct 25;50(42):9023-35. Epub 2011 Sep 30 PubMed.
Do HN, Devkota S, Bhattarai A, Wolfe MS, Miao Y. Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein. Commun Biol. 2023 Feb 14;6(1):174. 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.
Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.
Landman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, Park MK, Di Paolo G, Chung S, Kim TW. Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19524-9. PubMed.
Oh HG, Chun YS, Kim Y, Youn SH, Shin S, Park MK, Kim TW, Chung S. Modulation of transient receptor potential melastatin related 7 (TRPM7) channel by presenilins. Dev Neurobiol. 2011 Nov 18; PubMed.
Yang M, Wang Y, Liang G, Xu Z, Chu CT, Wei H. Alzheimer's Disease Presenilin-1 Mutation Sensitizes Neurons to Impaired Autophagy Flux and Propofol Neurotoxicity: Role of Calcium Dysregulation. J Alzheimers Dis. 2019;67(1):137-147. PubMed.
Hori A, Ai T, Hato T, Inaba H, Tanaka K, Okamoto M, Horiuchi Y, Paran FJ, Tabe Y, Rosales C, Akamatsu W, Murayama T, Sakurai T, Miida T. Carvedilol suppresses ryanodine receptor-dependent Ca2+ bursts in human neurons bearing PSEN1 variants found in early onset Alzheimer's disease. 2023 Sep 16 10.1101/2023.09.15.558029 (version 1) bioRxiv.
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 L286V

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