2. Academic Validation
  3. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis

A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis

  • J Exp Med. 2017 Sep 4;214(9):2547-2562. doi: 10.1084/jem.20161810.
Tobias Schwerd 1 2,  Stephen R F Twigg 3,  Dominik Aschenbrenner 1,  Santiago Manrique 4,  Kerry A Miller 3,  Indira B Taylor 3,  Melania Capitani 1,  Simon J McGowan 5,  Elizabeth Sweeney 6,  Astrid Weber 6,  Liye Chen 7,  Paul Bowness 7,  Andrew Riordan 8,  Andrew Cant 9,  Alexandra F Freeman 10,  Joshua D Milner 11,  Steven M Holland 10,  Natalie Frede 12,  Miryam Müller 13,  Dirk Schmidt-Arras 13,  Bodo Grimbacher 12 14,  Steven A Wall 15,  E Yvonne Jones 4,  Andrew O M Wilkie 16 15,  Holm H Uhlig 17 18
Affiliations

Affiliations

  • 1 Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
  • 2 Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 3 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
  • 4 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England, UK.
  • 5 Computational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
  • 6 Department of Clinical Genetics, Liverpool Women's National Health Service Foundation Trust, Liverpool, England, UK.
  • 7 Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, England, UK.
  • 8 Department of Paediatric Infectious Diseases and Immunology, Alder Hey Children's National Health Service Foundation Trust, Liverpool, England, UK.
  • 9 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, England, UK.
  • 10 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 11 Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • 12 Center for Chronic Immunodeficiency, Universitätsklinikum Freiburg, Freiburg, Germany.
  • 13 Inflammation and Cancer Lab, Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
  • 14 Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, England, UK.
  • 15 Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
  • 16 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England, UK [email protected].
  • 17 Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, England, UK [email protected].
  • 18 Department of Paediatrics, University of Oxford, Oxford, England, UK.
PMID: 28747427 DOI: 10.1084/jem.20161810
Abstract

Multiple cytokines, including interleukin 6 (IL-6), IL-11, IL-27, oncostatin M (OSM), and Leukemia Inhibitory Factor (LIF), signal via the common GP130 cytokine receptor subunit. In this study, we describe a patient with a homozygous mutation of IL6ST (encoding GP130 p.N404Y) who presented with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response, as well as skeletal abnormalities including craniosynostosis. The p.N404Y missense substitution is associated with loss of IL-6, IL-11, IL-27, and OSM signaling but a largely intact LIF response. This study identifies a novel immunodeficiency with phenotypic similarities to STAT3 hyper-IgE syndrome caused by loss of function of GP130.

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