Mutations

PSEN1 L250S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659552 T>C
dbSNP ID: rs63751163
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TCG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a screening of the British St. Mary’s and National hospitals’ collection of familial AD pedigrees (Hutton et al., 1996). Clinical information from five family members revealed a median age of onset of 52 years, with duration varying between six and 15 years. Three patients presented with pronounced myoclonus (without seizures), depression, and psychosis (Harvey et al., 1998).

Neuropathology
In two cases, neuropathology was consistent with AD (Harvey et al., 1998).

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed PSEN1 L250S generates less Aβ40 and Aβ42 peptides than the wild-type protein, and increases the Aβ42/Aβ40 ratio 10-fold (Sun et al., 2017).

Last Updated: 27 Mar 2019

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References

Paper Citations

  1. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  2. . Chromosome 14 familial Alzheimer's disease: the clinical and neuropathological characteristics of a family with a leucine-->serine (L250S) substitution at codon 250 of the presenilin 1 gene. J Neurol Neurosurg Psychiatry. 1998 Jan;64(1):44-9. PubMed.
  3. . 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

Papers

  1. . Gamma-secretase activity of presenilin 1 regulates acetylcholine muscarinic receptor-mediated signal transduction. J Biol Chem. 2004 Feb 20;279(8):6455-64. PubMed.
  2. . Akt activity in presenilin 1 wild-type and mutation transfected human SH-SY5Y neuroblastoma cells after serum deprivation and high glucose stress. J Neurosci Res. 2001 Nov 1;66(3):448-56. PubMed.
  3. . Alzheimer's disease presenilin-1 exon 9 deletion and L250S mutations sensitize SH-SY5Y neuroblastoma cells to hyperosmotic stress-induced apoptosis. Neuroscience. 2000;95(2):593-601. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
  2. . Chromosome 14 familial Alzheimer's disease: the clinical and neuropathological characteristics of a family with a leucine-->serine (L250S) substitution at codon 250 of the presenilin 1 gene. J Neurol Neurosurg Psychiatry. 1998 Jan;64(1):44-9. PubMed.

Other mutations at this position

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