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

Liu, Hengrui; Forouhar, Farhad; Seibt, Tobias; Saneto, Russell; Wigby, Kristen; Friedman, Jennifer; Xia, Xin; Shchepinov, Mikhail S.; Ramesh, Sanath Kumar; Conrad, Marcus und Stockwell, Brent R. (2021): Characterization of a patient-derived variant of GPX4 for precision therapy. In: Nature Chemical Biology, Bd. 18, Nr. 1: S. 91-100

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1552-4450
• Sprache: Englisch