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J Exp Med. 2020 Mar 2;217(3). pii: e20191306. doi: 10.1084/jem.20191306.

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.

Author information

Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
University and Regional Laboratories Department of Clinical Genetics, Lund, Sweden.
Department of Clinical Sciences, Pediatrics, Skåne University Hospital Lund, Lund University, Lund, Sweden.
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Celgene, Cambridge, MA.
Department of Clinical Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris cité, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.
Department of Obstetrics and Gynecology, Skåne University Hospital, Lund University, Lund, Sweden.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Sweden.
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Huddinge, Sweden.
Institute for Regenerative Medicine, Sechenov University, Moscow, Russian Federation.
Center for Intractable Diseases, Saitama University Hospital, Saitama, Japan.
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Department of Paediatrics, University of Oxford, Oxford, UK.
Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK.


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 Stüve-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.


Conflict of interest statement

Disclosures: Dr. Chen reported grants from Celgene during the conduct of the study and grants from Celgene outside the submitted work. Dr. Devey is an employee and stockholder of Celgene and is a former employee and stockholder of GlaxoSmithKline. Dr. Shanmugasundaram is an employee and stockholder of Celgene and a stockholder of Pfizer. Celgene has now become a wholly-owned subsidiary of Bristol-Myers Squibb. Dr. Aschenbrenner reported grants from UCB Pharma GmbH and grants from Eli Lilly and Company outside the submitted work. Dr. Uhlig reported grants from Celgene during the conduct of the study, grants from UCB Pharma, grants from Eli Lilly, personal fees from AbbVie, personal fees from Pfizer, and "other" from Regeneron outside the submitted work. No other disclosures were reported.

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