Mutations

PSEN1 P284S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37 (105)
Position: Chr14:73664819 C>T
dbSNP ID: rs63750324
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to TCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in four members of a family in whom affected members presented with dementia, spastic paraparesis, and white-matter lesions (Marrosu et al., 2006). Memory impairment and personality changes characterized the onset of disease, which ranged between 32 and 45 years of age. In addition, motor impairments, including spastic paraparesis, emerged early on. All mutation carriers had an APOE 3/3 genotype. The mutation was absent from 96 patients with sporadic multiple sclerosis and 96 unrelated, healthy controls.

Neuropathology

Neuropathological data are unavailable. However, MRI scans from four individuals revealed disseminated white-matter lesions reminiscent of those found in multiple sclerosis (Marrosu et al., 2006). Areas of hyperintensity in the frontal and temporal lobes were similar to those seen in cerebral autosomal-dominant arteriopathy (CADASIL), but no subcortical lacunar lesions typical of CADASIL were observed. Two subjects demonstrated multiple microbleeds in lobar regions (Floris et al., 2015).

Biological Effect

In an in vitro assay using the APP-C99 substrate, the mutant protein produced Aβ40 and Aβ42 peptides at levels similar to those generated by wild-type PSEN1. Accordingly, the Aβ42/Aβ40 ratio was similar to controls (Sun et al., 2017).

Last Updated: 09 Apr 2019

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References

Paper Citations

  1. . Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology. 2006 Jan 10;66(1):108-11. PubMed.
  2. . Multiple Spontaneous Cerebral Microbleeds and Leukoencephalopathy in PSEN1-Associated Familial Alzheimer's Disease: Mirror of Cerebral Amyloid Angiopathy?. J Alzheimers Dis. 2015;47(3):535-8. 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology. 2006 Jan 10;66(1):108-11. PubMed.

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