Mutations

PSEN1 G266S

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic, Cerebral Amyloid Angiopathy : Not Classified
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
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 who were past the mean age of onset, nor in 200 healthy controls nor 200 sporadic AD patients. Morevoer, it was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

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). Moreover, several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Last Updated: 03 Dec 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

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.
  5. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  6. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

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.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.