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

Publication Type:

Journal Article

Source:

Nat Chem Biol, Volume 18, Issue 1, p.91-100 (2022)

Keywords:

Humans, Phospholipid Hydroperoxide Glutathione Peroxidase, Point Mutation, Precision Medicine, Proof of Concept Study

Abstract:

<p>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.</p>

PDB: 
7L8K, 7L8L, 7L8M, 7L8R, and 7L8Q
Detector: 
EIGER2
Beamline: 
24-ID-C