Mutations

PSEN1 G378R

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype:
Reference Assembly: GRCh37/hg19
Position: Chr14:73683836 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGA to CGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This variant was identified in a genetic screen of 103 Spanish patients with early onset Alzheimer’s disease (AD) or fronto-temporal dementia (Ramos-Campoy et al., 2020). Whole-exome sequencing revealed the variant in a 50-year-old Spanish woman with dementia who had been suffering from episodic memory lapses, diminished language fluency, and word-finding difficulties for four years. Her APOE genotype was E3/E3. Of note, her mother’s cognition began declining at age 50, and that of her maternal uncle at age 58. The mutation was absent from the gnomAD variant database.

Neuropathology
Neuropathological data are unavailable, but a brain MRI of the proband revealed bilateral, fronto-temporo-parietal atrophy. Measurements of cerebrospinal fluid biomarkers were consistent with AD.

Biological Effect
The biological effects of this variant are unknown, but several in silico algorithms predicted the substitution to be deleterious, including SIFT, Polyphen-2, LRT, Mutation Taster, Mutation Assessor, FATHMM, LR, and Radial SVM (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 (Ramos-Campoy et al., 2020Xiao et al., 2021). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that G378 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for cleavage (Zhou et al., 2019; Jan 2019 news).

Following the ACMG guidelines (Richards et al., 2015), Ramos-Campoy and colleagues classified it as likely pathogenic (Ramos-Campoy et al., 2020).

Last Updated: 13 Sep 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. . Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.
  2. . 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.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.

Other mutations at this position

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.