Mutations

PSEN1 R278S

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664803 A>C
dbSNP ID: rs63750524
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGA to AGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a woman with a family history of dementia and spastic paraplegia (Raman et al., 2007). The proband developed progressive difficulties walking, poor balance, and slurred speech at age 39, and within a year, began experiencing memory impairment. By age 42, she had lower limb spasticity and weakness with bilateral Babinski signs, as well as upper extremity hyperreflexia. She also had impaired visual and verbal anterograde memory, and performed poorly on visuospatial tasks. Four additional affected family members, spanning three generations, had similar neurological presentations, and the family history was consistent with autosomal dominant inheritance. 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
Unknown

Biological Effect
Although the biological effect of this mutation is unknown, other mutations at this site have been reported to impair γ-secretase activity. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that R278 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for APP cleavage (Zhou et al., 2019; Jan 2019 news).

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).

Last Updated: 13 Sep 2021

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References

News Citations

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

Paper Citations

  1. . A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis. J Neurol Sci. 2007 Sep 15;260(1-2):78-82. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis. J Neurol Sci. 2007 Sep 15;260(1-2):78-82. PubMed.

Other mutations at this position

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