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

Abstract

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 (SSMD). With 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 PUFA were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations for therapeutic strategies targeting GPX4.

Icariin alleviates uveitis by targeting peroxiredoxin 3 to modulate retinal microglia M1/M2 phenotypic polarization

“…5 A). Among them, glutathione peroxidase 4 (GPX4) is the main enzyme involved in glutathione metabolism and diminishing phospholipid hydroperoxides within a cellular environment [ 24 ], which is consistent with the results of the KEGG analysis of ICA-binding proteins, as shown in Fig. 3 G. Thus, we focused on the GPX4 signalling pathway.…”

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

“…Four SSMD-linked truncating mutations in GPX4 have been described, associated with complete loss of Review GPX4 protein and death shortly after birth. Recently, a partial loss-of-function point mutation in GPX4 (R152H) was identified, which results in impaired enzymatic activity, but not a complete loss of function (Liu et al, 2022). This variant, unlike previous GPX4 variants associated with SSMD, is compatible with survival, albeit with a developmental impact (Figure 3).…”

The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities

“…In 1991, primary structure studies revealed that PHGPX was a new selenoprotein distinct but related to GPX-1, allowing PHGPX to be considered a new member of the glutathione peroxidase family [58]. Today, PDHGPX is known as GPX4 and is recognized as a key mediator of a variety of human diseases including certain cancers, neurodegenerative disorders, and rare genetic disorders [59]. There are several key features that make GPX4 unique from the other enzymes in the GPX family including its monomeric structure, its unique ability to reduce complex lipid hydroperoxides specifically, its broader substrate specificity, its vital role in early mouse development, and its involvement in an impressive variety of biological processes [60].…”

“…Ferroptosis is relevant to a multitude of diseases as discussed later in this review. In a recent paper, GPX4 was implicated in a rare genetic disorder called Sedaghatian-type Spondyloepiphyseal Dysplasia (SSMD) [59]. The CureGPX4 organization was recently developed to identify and develop treatments for GPX4 related diseases, such as SSMD.…”