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Liu, H.* ; Forouhar, F.* ; Seibt, T.* ; Saneto, R.* ; Wigby, K.* ; Friedman, J.* ; Xia, X.* ; Shchepinov, M.S.* ; Ramesh, S.K.* ; Conrad, M. ; Stockwell, B.R.*

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

Nat. Chem. Biol. 18, 91-100 (2022)
Postprint DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell-death; Selenium Supplementation; Oxidative Damage; Cancer-cells; Glutathione; Expression; Mutant; Dependency; Protects
Language english
Publication Year 2022
Prepublished in Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 1552-4450
e-ISSN 1552-4469
Journal Nature Chemical Biology
Quellenangaben Volume: 18, Issue: 1, Pages: 91-100 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Basingstoke
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
Grants U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
NINDS NIH HHS
NCI NIH HHS
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
DOI 10.1038/s41589-021-00915-2
WOS ID WOS:000731826400001
Scopus ID 85121564729
PubMed ID 34931062
Erfassungsdatum 2022-01-21
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