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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
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.
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Submitted on : Tuesday, April 21, 2020 - 3:31:27 PM
Last modification on : Tuesday, May 12, 2020 - 1:36:12 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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