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Université de Versailles Saint-Quentin-en-Yvelines

Journal articles

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 A. 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 G. 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 (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 [Oxford]

9 Garvan Institute of medical research

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 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 Hanover 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 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 AP-HP - Hopital Saint-Louis [AP-HP]

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 : Immunodeficiency Human disease genetics

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Immunology

Complete list of metadata

https://hal.uvsq.fr/hal-02549533
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Submitted on : Tuesday, April 21, 2020 - 3:31:27 PM
Last modification on : Tuesday, September 13, 2022 - 9:48:07 AM