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

Author:

Schwerd Tobias12ORCID,Twigg Stephen R.F.3ORCID,Aschenbrenner Dominik1,Manrique Santiago4,Miller Kerry A.3ORCID,Taylor Indira B.3,Capitani Melania1,McGowan Simon J.5ORCID,Sweeney Elizabeth6,Weber Astrid6,Chen Liye7,Bowness Paul7ORCID,Riordan Andrew8,Cant Andrew9,Freeman Alexandra F.10ORCID,Milner Joshua D.11ORCID,Holland Steven M.10,Frede Natalie12,Müller Miryam13,Schmidt-Arras Dirk13ORCID,Grimbacher Bodo1214,Wall Steven A.15,Jones E. Yvonne4ORCID,Wilkie Andrew O.M.315ORCID,Uhlig Holm H.116ORCID

Affiliation:

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. 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.

Funder

Medical Research Council

Weatherall Institute of Molecular Medicine

Department of Health

Wellcome Trust

Crohn’s and Colitis Foundation of America

Leona M. and Harry B. Helmsley Charitable Trust

ForCrohns

Crohn’s and Colitis UK

European Society for Paediatric Gastroenterology Hepatology and Nutrition

Deutsche Forschungsgemeinschaft

Bundesministeriums für Bildung und Forschung

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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