Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 217, Issue 3, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20191306
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Funding
- National Institute for Health Research Oxford Biomedical Research Centre
- Stockholm County Council [ALF20150143, 20180131]
- Karolinska Institutet [ALF20150143, 20180131]
- Swedish Research Council
- H.K.H. Kronprinsessan Lovisas Forening for Barnasjukvard/Stiftelsen Axel Tielmans minnesfond
- Stiftelsen Sallskapet Barnavard
- Stiftelsen Promobilia
- Stiftelsen Frimurare Barnhuset i Stockholm
- Russian Science Foundation [19-15-00241]
- Biomedical Research Centre Oxford
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The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stave-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.
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