Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome-Reference-Cited by-同舟云学术

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

Published:2020-03-24 Issue:6 Volume:217 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Béziat Vivien¹²³^ORCID,Tavernier Simon J.⁴⁵^ORCID,Chen Yin-Huai⁶⁷^ORCID,Ma Cindy S.⁸⁹,Materna Marie¹²,Laurence Arian⁶⁷^ORCID,Staal Jens⁵^ORCID,Aschenbrenner Dominik⁶⁷,Roels Lisa⁴,Worley Lisa⁸⁹,Claes Kathleen¹⁰,Gartner Lisa⁶⁷^ORCID,Kohn Lisa A.¹¹^ORCID,De Bruyne Marieke¹⁰^ORCID,Schmitz-Abe Klaus¹²¹³¹⁴,Charbonnier Louis-Marie¹⁵¹⁶^ORCID,Keles Sevgi¹⁷^ORCID,Nammour Justine¹²^ORCID,Vladikine Natasha¹²^ORCID,Maglorius Renkilaraj Majistor Raj Luxman¹²,Seeleuthner Yoann¹²,Migaud Mélanie¹²^ORCID,Rosain Jérémie¹²,Jeljeli Mohamed¹⁸,Boisson Bertrand¹²³^ORCID,Van Braeckel Eva¹⁹^ORCID,Rosenfeld Jill A.²⁰^ORCID,Dai Hongzheng²⁰^ORCID,Burrage Lindsay C.²⁰,Murdock David R.²⁰,Lambrecht Bart N.²¹²²^ORCID,Avettand-Fenoel Véronique²³^ORCID,Vogel Tiphanie P.²⁴^ORCID,Esther Charles R.²⁵,Haskologlu Sule²⁶^ORCID,Dogu Figen²⁶^ORCID,Ciznar Peter²⁷^ORCID,Boutboul David²⁸,Ouachée-Chardin Marie²⁹^ORCID,Amourette Jean³⁰,Lebras Marie-Noëlle³¹^ORCID,Gauvain Clément³²,Tcherakian Colas³³,Ikinciogullari Aydan²⁶,Beyaert Rudi⁵^ORCID,Abel Laurent¹²³^ORCID,Milner Joshua D.³⁴³⁵^ORCID,Grimbacher Bodo³⁶³⁷³⁸³⁹⁴⁰,Couderc Louis-Jean³³⁴¹,Butte Manish J.¹¹^ORCID,Freeman Alexandra F.³⁴^ORCID,Catherinot Émilie³³^ORCID,Fieschi Claire²⁸⁴²,Chatila Talal A.¹⁵¹⁶^ORCID,Tangye Stuart G.⁸⁹^ORCID,Uhlig Holm H.⁶⁷^ORCID,Haerynck Filomeen⁴⁴³^ORCID,Casanova Jean-Laurent¹²³⁴⁴⁴⁵^ORCID,Puel Anne¹²³^ORCID,

Affiliation:

1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France

2. University of Paris, Imagine Institute, Paris, France

3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY

4. Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium

5. VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Ghent, Belgium

6. Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK

7. Department of Paediatrics, University of Oxford, Oxford, UK

8. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia

9. St. Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia

10. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

11. Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA

12. Division of Newborn Medicine and Neonatal Genomics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA

13. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA

14. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA

15. Department of Pediatrics, Harvard Medical School, Boston, MA

16. Division of Immunology, Boston Children’s Hospital, Boston, MA

17. Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey

18. Cochin University Hospital, Biological Immunology Unit, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France

19. Department of Respiratory Medicine, Ghent University Hospital, Ghent Belgium

20. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX

21. VIB-UGent Center for Inflammation Research, Unit of Immunoregulation and Mucosal Immunology, Ghent, Belgium

22. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium

23. Laboratory of Clinical Microbiology, Virology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France

24. Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX

25. Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC

26. Division of Pediatric Immunology and Allergy, Ankara University School of Medicine, Sıhhıye, Ankara, Turkey

27. Department of Pediatrics, Faculty of Medicine Comenius University and Children's University Hospital, Bratislava, Slovakia

28. Clinical Immunology Department, Saint Louis Hospital, AP-HP de Paris University of Paris, Paris, France

29. Department of Pediatric Hematology and Immunology, Robert Debré Hospital, AP-HP, Paris, France

30. Pulmonology Department, Centre Hospitalier d'Arras, Arras, France

31. Pediatric Pulmonology, Infectious Disease and Internal Medicine Department, AP-HP, Robert Debré Hospital, Paris, France

32. Thoracic Oncology Department, Lille University Hospital, Lille, France

33. Hôpital Foch, Pulmonology Department, Suresnes, France

34. National Institute of Allergy and Infectious Diseases, Bethesda, MD

35. Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY

36. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany

37. German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany

38. Centre for Integrative Biological Signaling Studies, Albert Ludwig University, Freiburg, Germany

39. RESIST, Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany

40. Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK

41. Simone Veil Faculty of Life Sciences, Versailles-Paris Saclay University, UPRES EA-220, Suresnes, France

42. INSERM UMR1126, Institut de Recherche Saint-Louis, Université de Paris, Paris, France

43. Department of Internal Medicine and Pediatrics, Division of Pediatric Immunology and Pulmonology, Ghent University Hospital, Ghent, Belgium

44. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France

45. Howard Hughes Medical Institute, New York, NY

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.

Funder

St. Giles Foundation

Rockefeller University

Institut National de la Santé et de la Recherche Médicale

Paris Descartes University

Howard Hughes Medical Institute

Job Research Foundation

French National Research Agency

French Foundation for Medical Research

Jeffrey Model Foundation

Yale Center for Mendelian Genomics

National Human Genome Research Institute