A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis PMID: 28747427

ADC Targets in Oncology

2026-04-10

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

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.

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.