Mutations

PSEN1 G266S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy : Pathogenic
Clinical Phenotype: Spastic Paraparesis, Alzheimer's Disease, Cerebral Amyloid Angiopathy
Reference Assembly: GRCh37 (105)
Position: Chr14:73664765 G>A
dbSNP ID: rs121917807
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to AGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a family of Japanese origin with six affected individuals spanning two generations (Matsubara-Tsutsui et al., 2002). The initial symptoms were spastic paraparesis and apraxia followed by dementia, with a mean age of onset of 45 years. The mutation was detected in the proband, but not in three unaffected family members, nor in 200 healthy controls nor 200 sporadic AD patients.

Neuropathology
An autopsy of a 52-year-old mutation carrier revealed neuropathology consistent with AD, including marked atrophy of the temporal and frontal lobes. In addition, numerous cotton-wool plaques were found in the cerebral cortex with accompanying cerebral amyloid angiopathy. Also, widespread neurofibrillary tangles were observed, as well as reactive gliosis in the white matter (Akatsu et al., 2008). MRI in another patient revealed atrophy of the cerebral cortex, particularly of the parietal lobes, and abnormalities in the deep white matter of the frontal lobes and areas surrounding the lateral ventricles (Matsubara-Tsutsui et al., 2002). SPECT showed marked hypoperfusion in parietal and occipital areas, typical of AD.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates less Aβ42, and much less Aβ40, than wild-type PSEN1, resulting in an approximately 10-fold elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017). The amino acid position is conserved across species and related proteins, including mouse PSEN1, human PSEN2, C. elegans Spe-4, and C. elegans Sel-12 (Matsubara-Tsutsui et al., 2002). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue appears to help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

Last Updated: 14 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Molecular evidence of presenilin 1 mutation in familial early onset dementia. Am J Med Genet. 2002 Apr 8;114(3):292-8. PubMed.
  2. . The first autopsy case report of familial Alzheimer's disease (AD) associated with a mutation at G266S in the presenilin 1 (PSEN1) gene. Alzheimers Dement. 2008 Jul;4(4 Suppl);T578.
  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.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Molecular evidence of presenilin 1 mutation in familial early onset dementia. Am J Med Genet. 2002 Apr 8;114(3):292-8. PubMed.
  2. . The first autopsy case report of familial Alzheimer's disease (AD) associated with a mutation at G266S in the presenilin 1 (PSEN1) gene. Alzheimers Dement. 2008 Jul;4(4 Suppl);T578.

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