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

Research output: Contribution to journalArticle


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.


  • Yin Huai Chen
  • Giedre Grigelioniene
  • Phillip T. Newton
  • Jacob Gullander
  • Anna Hammarsjö
  • Dominyka Batkovskyte
  • Hessa S. Alsaif
  • Wesam I.Y. Kurdi
  • Firdous Abdulwahab
  • Veerabahu Shanmugasundaram
  • Luke Devey
  • Séverine Bacrot
  • Jana Brodszki
  • Celine Huber
  • Ben Hamel
  • Nikos Papadogiannakis
  • Katarina Jedrycha
  • Barbara Gürtl-Lackner
  • Andrei S. Chagin
  • Gen Nishimura
  • Dominik Aschenbrenner
  • Fowzan S. Alkuraya
  • Arian Laurence
  • Valérie Cormier-Daire
  • Holm H. Uhlig
External organisations
  • University of Oxford
  • Karolinska Institutet
  • Karolinska University Hospital
  • Skåne University Hospital
  • King Faisal Specialist Hospital and Research Centre
  • Celgene Corporation
  • Paris Descartes University
  • Radboud University Medical Center
  • Lund University
  • I.M. Sechenov First Moscow State Medical University
  • Saitama University
  • Alfaisal University
  • Necker-Enfants Malades Hospital
  • NIHR Biomedical Research Centre, Oxford
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Article numbere20191306
JournalThe Journal of experimental medicine
Issue number3
Publication statusPublished - 2020
Publication categoryResearch