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

Hengrui LiuFarhad ForouharTobias SeibtRussell SanetoKristen WigbyJennifer FriedmanXin XiaMikhail S ShchepinovSanath Kumar RameshMarcus ConradBrent R Stockwell
Published in: Nature chemical biology (2021)
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.
Keyphrases
  • fatty acid
  • genome wide
  • copy number
  • stem cells
  • single cell
  • gene expression
  • case report
  • dna methylation
  • transcription factor
  • cell therapy
  • small molecule
  • cancer therapy
  • bone marrow