Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome - Université de Versailles Saint-Quentin-en-Yvelines Access content directly
Journal Articles Journal of Experimental Medicine Year : 2020

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

1 St. Giles Laboratory of Human Genetics of Infectious Diseases
2 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
3 Necker Branch - INSERM U1163 - Laboratory of Human Genetics of Infectious Diseases
4 Ghent University Hospital
5 IRC - VIB-UGent Center for Inflammation Research [Gand, Belgique]
6 Center for Medical Genetics [Ghent]
7 John Radcliffe Hospital [Oxford University Hospital]
8 University of Oxford
9 Garvan Institute of medical research
10 St. Vincent’s Clinical School, Faculty of Medicine
11 UC - University of California
12 Boston Children's Hospital
13 HMS - Harvard Medical School [Boston]
14 Necmettin Erbakan University [Konya, Turquie]
15 Hôpital Cochin [AP-HP]
16 BCM - Baylor College of Medicine
17 Laboratoire de Virologie [CHU Necker]
18 UNC - University of North Carolina [Chapel Hill]
19 Ankara University School of Medicine [Turkey]
20 Comenius University in Bratislava
21 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
22 Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris]
23 Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras
24 Service de pneumologie [Hôpital Foch]
25 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
26 CUIMC - Columbia University Irving Medical Center
27 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
28 Centre for Integrative Biological Signaling Studies [Freiburg, Germany]
29 MHH - Medizinische Hochschule Hannover = Hannover Medical School
30 LOBIP - Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique
31 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
32 Keck School of Medicine [Los Angeles]
33 IRSL - Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)
34 AP-HP - Hopital Saint-Louis [AP-HP]
35 Boston Children's Hospital
36 St. Vincent’s Clinical School [Sydney, Australia]
37 Hôpital Necker - Enfants Malades [AP-HP]
Jill A. Rosenfeld
  • Function : Author
  • PersonId : 906001
Clément Gauvain
  • Function : Author
Filomeen Haerynck
  • Function : Author
  • PersonId : 892234


Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.


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Dates and versions

hal-02549533 , version 1 (07-06-2023)




Vivien Beziat, Simon Tavernier, Yin-Huai Chen, Cindy Ma, Marie Materna, et al.. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. Journal of Experimental Medicine, 2020, 217 (6), ⟨10.1084/jem.20191804⟩. ⟨hal-02549533⟩
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