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

Vivien Beziat 1, 2, 3 Simon Tavernier 4, 5, 6 Yin-Huai Chen 7, 8 Cindy Ma 9, 10 Marie Materna 2, 3 Arian Laurence 7, 8 Jens Staal 5 Dominik Aschenbrenner 7, 8 Lisa Roels 4, 6 Lisa Worley 9, 10 Kathleen Claes 4, 6 Lisa Gartner 7, 8 Lisa Kohn 11 Marieke de Bruyne 6, 4 Klaus Schmitz-Abe 12, 13 Louis-Marie Charbonnier 13, 12 Sevgi Keles 14 Justine Nammour 3, 2 Natasha Vladikine 2, 3 Majistor Raj Luxman Maglorius Renkilaraj 3, 2 Yoann Seeleuthner 3, 2 Mélanie Migaud 3, 2 Jeremie Rosain 3, 2 Mohamed Jeljeli 15 Bertrand Boisson 3, 2, 1 Eva van Braeckel 4 Jill Rosenfeld 16 Hongzheng Dai 16 Lindsay Burrage 16 David Murdock 16 Bart Lambrecht 5, 4 Véronique Avettand-Fenoël 17 Tiphanie Vogel 16 Charles Esther 18 Sule Haskologlu 19 Figen Dogu 19 Peter Ciznar 20 David Boutboul 21 Marie Ouachée-Chardin 22 Jean Amourette 23 Marie-Noëlle Lebras 22 Clément Gauvain Colas Tcherakian 24 Aydan Ikinciogullari 19 Rudi Beyaert 5 Laurent Abel 3, 2, 1 Joshua Milner 25, 26 Bodo Grimbacher 27, 28, 29 Louis-Jean Couderc 30, 31, 24 Manish Butte 32 Alexandra Freeman 25 Emilie Catherinot 24 Claire Fieschi 33, 34 Talal Chatila 13, 35 Stuart Tangye 9, 36 Holm Uhlig 7, 8 Filomeen Haerynck 4 Jean-Laurent Casanova 3, 2, 1, 37 Anne Puel 3, 2, 1
1 St. Giles Laboratory of Human Genetics of Infectious Diseases
2 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
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 [Oxford]
9 Garvan Institute of Medical Research [Darlinghurst, Australia]
10 St. Vincent’s Clinical School, Faculty of Medicine
11 University of California
12 Boston Children's Hospital
13 HMS - Harvard Medical School [Boston]
14 Necmettin Erbakan University [Konya, Turquie]
15 CHU 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 [Bratislava]
21 Service d'Immunopathologie [Hôpital Saint-Louis, Paris]
22 Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris]
23 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 Hanover Medical School
30 LOBIP - Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique
31 UVSQ UFR Santé - UFR des sciences de la santé Simone Veil
32 Department of Pediatrics, Keck School of Medicine, University of Southern California, 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 Hôpital Saint-Louis
35 Boston Children's Hospital
36 St. Vincent’s Clinical School [Sydney, Australia]
37 CHU Necker - Enfants Malades [AP-HP]
Abstract : 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.
Keywords : Human disease genetics Immunodeficiency
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Journal articles
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https://hal.uvsq.fr/hal-02549533
Contributor : Équipe Hal Uvsq <>
Submitted on : Tuesday, April 21, 2020 - 3:31:27 PM
Last modification on : Monday, July 20, 2020 - 11:52:13 AM

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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, Rockefeller University Press, 2020, 217 (6), ⟨10.1084/jem.20191804⟩. ⟨hal-02549533⟩

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