Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664825 C>G
dbSNP ID: rs63751235
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8
Research Models: 11


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. 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.


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

Biological Effect

In HEK-293 cells transfected with APP with the Swedish mutation, the L286V mutation was found to increase the Aβ42/Aβ total ratio (Citron et al., 1997; Kulic et al., 2000). A similar effect was seen in COS-1 cells transfected with APP695—compared with cells expressing wild-type PSEN1, the L286V mutation increased the Aβ42/Aβ total ratio (Murayama et al., 1999). Consistent with these findings, in vitro experiments with purified proteins revealed decreased Aβ40 and increased Aβ42 production (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates 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).

Although the mutation does not appear to affect Notch endoproteolysis (Kulic et al., 2000; Ikeuchi et al., 2008), it may have other effects beyond APP processing. In particular, the mutation has been reported to disrupt intracellular calcium dynamics (see Dec 2006 news; Landman et al., 2006; Oh et al., 2012; Yang et al., 2019).

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).

Last Updated: 04 Aug 2019


No Available Comments

Make a Comment

To make a comment you must login or register.


News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding
  2. Beyond γ-Secretase: FAD Mutations Affect Calcium Channel via Lipid Messenger

Paper Citations

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
  2. . Familial Alzheimer disease: a large, multigeneration German kindred. Alzheimer Dis Assoc Disord. 1991;5(1):36-43. PubMed.
  3. . 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.
  4. . Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997 Jan;3(1):67-72. PubMed.
  5. . 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.
  6. . 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.
  7. . 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.
  8. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  9. . 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.
  10. . Modulation of transient receptor potential melastatin related 7 (TRPM7) channel by presenilins. Dev Neurobiol. 2011 Nov 18; PubMed.
  11. . 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.

Other Citations

  1. 5xFAD

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.

Other mutations at this position


Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.