Mutations

PSEN1 T440del

Overview

Pathogenicity: Parkinson's Disease Dementia : Pathogenic, Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Dementia with Lewy Bodies
Reference Assembly: GRCh37 (105)
Position: Chr14:73685910 ACC>---
dbSNP ID: rs63750470
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: ACC to ---
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was discovered in a Japanese man with a family history of parkinsonism and dementia (Ishikawa et al., 2005). The proband first developed parkinsonism, which was responsive to L-dopa, at age 34. At age 41, cognitive decline and generalized dystonia set in. Dementia progressed rapidly. At age 52, the patient died of respiratory infection. The father and grandfather of the proband also suffered from parkinsonism and died in their late 40s. Of note, the father developed dementia first, followed by parkinsonism nine years later. The proband was the only family member genotyped. No additional mutations were found in the coding regions and exon-intron junctions of APP, PSEN1, PSEN2, nor in those of α-, β-, and γ-synuclein. Moreover, the T441 deletion was absent from eight patients with familial dementia with Lewy bodies, 50 patients with sporadic AD, and 94 healthy Japanese controls. 

Neuropathology

Neuropathological examination of the proband's brain revealed neuronal loss in several brain regions, including the substantia nigra and cerebral cortex. In addition, the authors reported widespread Lewy bodies and cotton wool plaques, as well as corticospinal tract degeneration and cerebral amyloid angiopathy. 

Based on guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (McKeith et al., 1996), the patient was classified as having Parkinson's disease with dementia of the neocortical subtype. He was also described as meeting the pathological criteria for variant AD.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed abrogation of Aβ40 production and a dramatic reduction of Aβ42 production. In addition, autoproteolysis of PSEN1 was nearly abolished (Sun et al., 2017).

Last Updated: 19 Sep 2019

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References

Paper Citations

  1. . A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.
  2. . Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996 Nov;47(5):1113-24. 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.

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