PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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.
Impact Factor
Scopus SNIP
Scopus
Cited By
Altmetric
16.174
2.795
16
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cell-death; Selenium Supplementation; Oxidative Damage; Cancer-cells; Glutathione; Expression; Mutant; Dependency; Protects
Sprache englisch
Veröffentlichungsjahr 2022
Prepublished im Jahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1552-4450
e-ISSN 1552-4469
Zeitschrift Nature Chemical Biology
Quellenangaben Band: 18, Heft: 1, Seiten: 91-100 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Basingstoke
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-506900-001
Förderungen 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
[➜Korrektur melden]