Mutations

PSEN1 N405S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683918 A>G
dbSNP ID: rs63751254
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AAC to AGC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was found in a Japanese woman with early onset AD (Yasuda et al., 2000). The woman developed memory impairment at age 48, and progressed rapidly to dementia with spasticity within a year, eventually becoming motionless and mute and dying at age 53. She had no known family history of dementia. The mutation was absent from 100 controls and 100 cases of sporadic AD.

Neuropathology
Neuropathology of this single case was consistent with AD, with minimal cerebral amyloid angiopathy.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 and Aβ42 production, and a decreased Aβ42/Aβ40 ratio (Sun et al., 2017).

Last Updated: 15 May 2019

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References

Paper Citations

  1. . Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PubMed.
  2. . 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. . Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry. 2000 Feb;68(2):220-3. PubMed.

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