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

Tobias Schwerd; Stephen R F Twigg; Dominik Aschenbrenner; Santiago Manrique; Kerry A Miller; Indira B Taylor; Melania Capitani; Simon J McGowan; Elizabeth Sweeney; Astrid Weber; Liye Chen; Paul Bowness; Andrew Riordan; Andrew Cant; Alexandra F Freeman; Joshua D Milner; Steven M Holland; Natalie Frede; Miryam Müller; Dirk Schmidt-Arras; Bodo Grimbacher; Steven A Wall; E Yvonne Jones; Andrew O M Wilkie; Holm H Uhlig

doi:10.1084/jem.20161810

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. Epub 2017 Jul 26.

Authors

Tobias Schwerd^{1

2}, Stephen R F Twigg³, Dominik Aschenbrenner¹, Santiago Manrique⁴, Kerry A Miller³, Indira B Taylor³, Melania Capitani¹, Simon J McGowan⁵, Elizabeth Sweeney⁶, Astrid Weber⁶, Liye Chen⁷, Paul Bowness⁷, Andrew Riordan⁸, Andrew Cant⁹, Alexandra F Freeman¹⁰, Joshua D Milner¹¹, Steven M Holland¹⁰, Natalie Frede¹², Miryam Müller¹³, Dirk Schmidt-Arras¹³, Bodo Grimbacher^{12

14}, Steven A Wall¹⁵, E Yvonne Jones⁴, 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.

MeSH terms

Child, Preschool
Craniosynostoses / genetics*
Cytokine Receptor gp130 / genetics*
Cytokine Receptor gp130 / physiology
Exome / genetics
Female
Humans
Immunologic Deficiency Syndromes / genetics*
Interleukin-11 / deficiency
Interleukin-6 / deficiency
Interleukins / deficiency
Mutation, Missense / genetics*

Substances

IL11 protein, human
IL6ST protein, human
Interleukin-11
Interleukin-6
Interleukins
MYDGF protein, human
Cytokine Receptor gp130

Associated data

RefSeq/NM_002184
RefSeq/NP_001106976.1
RefSeq/NP_001124412.1
RefSeq/NP_990202.1
RefSeq/NP_034690.3
RefSeq/NP_002175.2
RefSeq/NP_004834.1
RefSeq/NP_000751.1
RefSeq/NP_002301.1
RefSeq/NP_003990.1
RefSeq/NP_005526.1
RefSeq/NP_001550.1
PDB/1P9M
PDB/3L5H

Abstract

MeSH terms

Substances

Associated data

Grants and funding