Mutations

PSEN1 L435F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
dbSNP ID: rs63750001
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: CTT to TTT

Findings

This mutation was first reported in one out of 414 people with suspected Alzheimer's disease. However, no clinical, neuropathological, or family details were reported (Rogaeva et al., 2001).

The L435F mutation was subsequently identified in two siblings with a family history of early onset AD (Heilig et al., 2010). The reported pedigree shows a third affected sibling, as well as their affected father. The average age of onset was 47 years, and the average age at death was 56 years. Disease in this family presented as early and progressive memory problems and aphasia. Motor symptoms, including parkinsonism, developed later, but not spastic paraparesis. Segregation with disease was suggested by the fact that the mutation was found in both of the affected siblings tested.

Neuropathology

Neuropathological analysis of the two affected mutation carriers showed numerous and widespread cotton-wool plaques throughout the neocortex, hippocampus, and deep cerebral nuclei. These large plaques lacked a dense core and were associated with neuritic dystrophy. Some neurofibrillary tangles were observed in the cortex, with high concentrations in the entorhinal cortex and hippocampus. Evidence of mild cerebral amyloid angiopathy was present in vessels. The substantia nigra was affected by neuronal loss, depigmentation, and gliosis (Heilig et al., 2010).

Biological Effect

In vitro, this mutation was found to cause a loss of γ-secretase activity. It nearly abolished the cleavage of multiple γ-secretase substrates, including APP and Notch, resulting in dramatically reduced levels of proteolytic products, including APP-CTFs, Aβ40, and Aβ42. The mutant presenilin-1 was appropriately trafficked to the cell surface, but endoproteolysis of the holo-protein was impaired, which is thought to account for the loss of secretase activity (Heilig et al., 2010).

Research Models

Heterozygous knockin mice carrying human presenilin-1 with the L435F mutation develop deficits in synaptic plasticity and memory as well as age-related neurodegeneration. The mutant presenilin-1 was associated with a loss of γ-secretase activity in vivo, leading to perinatal lethality in homozygous mice (Xia et al., 2015).

Comments

Comments on this content

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015 Mar 4;85(5):967-81. PubMed.
  2. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  3. . A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. PubMed.

Further Reading

Papers

  1. . Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci. 2013 Jul 10;33(28):11606-17. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.