Mutations

PSEN1 I83_M84del (DelIM)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease
Reference Assembly: GRCh37 (105)
dbSNP ID: rs63750307
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: ATC.ATG to ---.---
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This hexanucelotide deletion was identified in a large Scottish family known as EB with five affected members across three generations. Affected family members presented first with spastic paraparesis, followed by cognitive decline attributed to early onset Alzheimer's disease. The mean age of onset for spastic paraparesis was 36 years (range: 34 to 38 years). This mutation involves deletion of codons 83 and 84 resulting in removal of isoleucine and methionine (Houlden et al., 2000).

Neuropathology

This mutation is associated with cotton-wool plaques similar to what was described in the family FINN2, whose affected members carry the ΔE9Finn mutation (PS1del9) (Crook et al., 1998). Plaques appeared in the neuropil as round, eosinophilic, and Aβ-positive structures often larger than 100 μm in diameter. Although Aβ-positive, they were generally noncongophilic, suggesting a lack of amyloid. Although widespread in the brain parenchyma, they were most abundant in the neocortex, hippocampus, and striatum. Cerebral amyloid angiopathy, neurofibrillary tangles, and neuropil threads were also noted (Steiner et al., 2001).

Biological Effect

This is a hexanucleotide deletion resulting in the loss of two amino acids (I and M). Cultured H4 glioma cells expressing mutant PSEN1 have an elevated Aβ42/Aβ40 ratio compared to cells transfected with wild-type PSEN1 (Houlden et al., 2000). A similar result was seen in HEK-293 cells expressing APP with the Swedish mutation: Introducing the PSEN1 I83_M84del mutation resulted in an increased Aβ42/Aβ40 ratio compared to wild-type PSEN1. Moreover, An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates reduced levels of Aβ42 compared with wild-type PSEN1 and Aβ40 production is undetectable (Sun et al., 2017). In addition, functional analysis in Caenorhabditis elegans indicated reduced activity of the mutant PSEN1 with respect to Notch signaling (Steiner et al., 2001).

Last Updated: 27 Aug 2019

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References

Mutations Citations

  1. PSEN1 S290C;T291_S319del (ΔE9Finn)

Paper Citations

  1. . Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000 Nov;48(5):806-8. PubMed.
  2. . A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
  3. . A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques. J Biol Chem. 2001 Mar 9;276(10):7233-9. Epub 2000 Nov 17 PubMed.
  4. . 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. . Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000 Nov;48(5):806-8. PubMed.
  2. . A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques. J Biol Chem. 2001 Mar 9;276(10):7233-9. Epub 2000 Nov 17 PubMed.

Other mutations at this position

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