Mutations

PSEN1 L381V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Genome Build: 105
Position: Chr14:73683845 C>G
dbSNP ID: rs63750687
Coding/Non-Coding: Coding
Genomic Region: Exon 11
Mutation Type: Point, Missense
Codon Change: CTT to GTT

Findings

This mutation was identified in the proband of a Bulgarian family with three members affected by Alzheimer's disease. The clinical course in this family was characterized by early onset, rapid progression, and some atypical features, such as extrapyramidal signs and spastic paraparesis. The proband developed symptoms at age 32 and died at age 37 (Mehrabian et al., 2004; Dintchov Traykov et al., 2009).

A Japanese family with the L381V mutation has also been described. The family, referred to as P3000, included a father and daughter with probable AD according to NINCDS-ADRDA criteria. The father died in his early 40s with severe dementia and progressive gait impairment. The daughter presented first with apathy at age 29, followed by progressive memory deficits and gait disturbance. Two years later she had also developed spastic paraparesis (Ikeuchi et al., 2008).

Neuropathology

Unknown.

Biological Effect

HEK293 cells stably expressing mutant PSEN1, secreted greater amounts of Aβ42, and had an elevated Aβ42/Aβ40 ratio. In these cells, the N-terminal fragment (NTF) of presenilin-1 was decreased, suggesting impaired endoproteolysis of the protein. NICD levels were decreased, suggesting reduced Notch cleavage by γ-secretase (Ikeuchi et al., 2008).

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References

Paper Citations

  1. . A novel PSEN1 mutation in an EOAD family with spastic paraparesis and extrapyramidal signs. European Journal of Neurology 11 Supp 2: 16, 2004.
  2. . Novel PSEN1 mutation in a Bulgarian patient with very early-onset Alzheimer's disease, spastic paraparesis, and extrapyramidal signs. Am J Alzheimers Dis Other Demen. 2009 Oct-Nov;24(5):404-7. 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Novel PSEN1 mutation in a Bulgarian patient with very early-onset Alzheimer's disease, spastic paraparesis, and extrapyramidal signs. Am J Alzheimers Dis Other Demen. 2009 Oct-Nov;24(5):404-7. PubMed.
  2. . A novel PSEN1 mutation in an EOAD family with spastic paraparesis and extrapyramidal signs. European Journal of Neurology 11 Supp 2: 16, 2004.

Other mutations at this position

Alzpedia