Mutations

PSEN1 L153V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640392 C>G
dbSNP ID: rs63751441
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTG to GTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first identified in two members of a French family with five individuals diagnosed with probable AD, spanning three generations (Raux et al., 2000). Age of onset ranged between 34 and 38 years of age. Symptoms were typical of AD, including early memory loss, spatial disorientation, and progressive deterioration of praxis and language. The mutation was absent from 50 unrelated Caucasian controls.

The mutation was also found in English and Peruvian kindreds, which similarly developed AD symptoms very early, starting in the mid-30s. The English family included three affected members, two with confirmed mutations, spanning three generations (Janssen et al. 2001). The Peruvian family included eight affected members, with four confirmed mutation carriers, across two generations (Cornejo-Olivas et al., 2014). The mutation was absent from one unaffected member in this family. Based on genotypic analyses, the Peruvian family’s mutation may have an Amerindian or African origin.

Although affected individuals in all families were diagnosed with probable AD, there was symptom variability. For example, the English family had one member with myoclonus and none with seizures or spasticity, whereas all three symptoms were reported in the Peruvian family.

Neuropathology
In one case, neuropathology was consistent with severe AD, including abundant neurofibrillary tangles, neuritic plaques, and neuropil threads in the hippocampus and cerebral cortex (Janssen et al. 2001). Extensive deposition of Aβ was seen in both the cerebral parenchyma and blood vessels. Moreover, occasional Lewy bodies were found in the trans-entorhinal, cingulate, insular, and parietal cortices.

Biological Effect

In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, Aβ42 production was drastically reduced and Aβ40 production was undetectable (Sun et al., 2017). The mutation affects an amino acid conserved in PSEN2 and in dps, the Drosophila melanogaster homolog of PSEN1.

Last Updated: 01 Apr 2019

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References

Paper Citations

  1. . A novel presenilin 1 missense mutation (L153V) segregating with early-onset autosomal dominant Alzheimer's disease. Hum Mutat. 2000 Jul;16(1):95. PubMed.
  2. . Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation. Arch Neurol. 2001 Jun;58(6):953-8. PubMed.
  3. . Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease. Neurosci Lett. 2014 Mar 20;563:140-3. Epub 2014 Feb 2 PubMed.
  4. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 missense mutation (L153V) segregating with early-onset autosomal dominant Alzheimer's disease. Hum Mutat. 2000 Jul;16(1):95. PubMed.
  2. . Autopsy-confirmed familial early-onset Alzheimer disease caused by the l153V presenilin 1 mutation. Arch Neurol. 2001 Jun;58(6):953-8. PubMed.

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