A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis,Journal of Experimental Medicine

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A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis
Journal of Experimental Medicine ( IF 15.3 ) Pub Date : 2017-07-26 , 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 _{15,

16} , Holm H Uhlig _{17,

18}

Affiliation

Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England, UK.
Computational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England, UK.
Department of Clinical Genetics, Liverpool Women's National Health Service Foundation Trust, Liverpool, England, UK.
Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, England, UK.
Department of Paediatric Infectious Diseases and Immunology, Alder Hey Children's National Health Service Foundation Trust, Liverpool, England, UK.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, England, UK.
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Center for Chronic Immunodeficiency, Universitätsklinikum Freiburg, Freiburg, Germany.
Inflammation and Cancer Lab, Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, England, UK.
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.
Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, England, UK
Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, England, UK
Department of Paediatrics, University of Oxford, Oxford, England, UK.

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.

中文翻译：

编码 GP130 共受体的 IL6ST 中的双等位基因突变导致免疫缺陷和颅缝早闭

多种细胞因子，包括白细胞介素 6 (IL-6)、IL-11、IL-27、制瘤素 M (OSM) 和白血病抑制因子 (LIF)，通过常见的 GP130 细胞因子受体亚基发出信号。在本研究中，我们描述了一名具有IL6ST（编码 GP130 p.N404Y）纯合突变的患者，该患者表现为反复感染、湿疹、支气管扩张、高 IgE、嗜酸性粒细胞增多、B 细胞记忆缺陷和急性期反应受损，如以及骨骼异常，包括颅缝早闭。p.N404Y 错义替换与 IL-6、IL-11、IL-27 和 OSM 信号的丢失有关，但 LIF 反应基本完好。该研究确定了一种新的免疫缺陷，其表型与由 GP130 功能丧失引起的 STAT3 高 IgE 综合征相似。

更新日期：2017-08-10

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