• About
    • Company Overview
    • Management Team
    • Board of Directors
    • Science Advisors
    • Neurology Advisors
    • Ophthalmology Advisors
    • Contacts
  • Science
    • Publications
    • Collaborators
  • Pipeline
    • Infantile Neuroaxonal Dystrophy (INAD)
    • Friedreich’s Ataxia (FA)
    • Amyotrophic Lateral Sclerosis (ALS)
    • Progressive Supranuclear Palsy (PSP)
    • Dry AMD
    • Future Targets
  • Patient Resources
    • Expanded Access Policy
    • Clinical Trials
    • Additional Resources
  • News & Events
    • Press Releases
    • News
    • Events
    • Videos
  • Careers
HomeScienceCharacterization of a patient-derived variant of GPX4 for precision therapy

Characterization of a patient-derived variant of GPX4 for precision therapy

Abstract

Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.

Read more…

About
Science
  • Publications
Pipeline
  • Clinical
  • Preclinical
  • Future Targets
Patient Resources
  • Expanded Access Policy
News & Events
Careers
RETROTOPE, 4300 EL CAMINO REAL, SUITE 201, LOS ALTOS, CA 94022
Copyright ©️ 2015-2021 Retrotope Inc.
You are leaving Retrotope’s website. Retrotope does not guarantee the accuracy or completeness of the information contained on any third-party sites, nor does it endorse any of the opinions or information contained on those sites. Please click CONFIRM to continue. CONFIRM