Characterization of a patient-derived variant of GPX4 for precision therapy.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
09
04
2021
accepted:
01
10
2021
pubmed:
22
12
2021
medline:
23
2
2022
entrez:
21
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34931062
doi: 10.1038/s41589-021-00915-2
pii: 10.1038/s41589-021-00915-2
pmc: PMC8712418
mid: NIHMS1745387
doi:
Substances chimiques
Phospholipid Hydroperoxide Glutathione Peroxidase
EC 1.11.1.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
91-100Subventions
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NINDS NIH HHS
ID : R61 NS109407
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA209896
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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