期刊
NATURE CHEMICAL BIOLOGY
卷 18, 期 1, 页码 91-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00915-2
关键词
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资金
- BMBF VIP+ program NEUROPROTEKT [03VP04260]
- Ministry of Science and Higher Education of the Russian Federation [075-15-2019-1933]
- European Research Council (ERC) under the European Union [GA 884754]
- [P01CA87497]
- [R35CA209896]
- [R61NS109407]
A homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, was identified in patients with Sedaghatian-type spondylometaphyseal dysplasia. The missense variant destabilized a critical loop in the enzyme, disrupting the active site and causing a loss of enzymatic function. Therapeutic treatments targeting the impaired R152H GPX4 activity were identified, including selenium supplementation, selective antioxidants, and a deuterated polyunsaturated fatty acid.
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.
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