Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance-Reference-Cited by-同舟云学术

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Published:2021-06-17 Issue:8 Volume:218 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Asano Takaki¹^ORCID,Khourieh Joëlle²³^ORCID,Zhang Peng¹^ORCID,Rapaport Franck¹^ORCID,Spaan András N.¹^ORCID,Li Juan¹^ORCID,Lei Wei-Te¹^ORCID,Pelham Simon J.¹^ORCID,Hum David¹^ORCID,Chrabieh Maya²³^ORCID,Han Ji Eun¹^ORCID,Guérin Antoine⁴⁵^ORCID,Mackie Joseph⁴⁵^ORCID,Gupta Sudhir⁶^ORCID,Saikia Biman⁷^ORCID,Baghdadi Jamila E.I.⁸^ORCID,Fadil Ilham⁹¹⁰^ORCID,Bousfiha Aziz⁹¹⁰^ORCID,Habib Tanwir¹¹^ORCID,Marr Nico¹¹¹²^ORCID,Ganeshanandan Luckshman¹³^ORCID,Peake Jane¹⁴^ORCID,Droney Luke¹⁵^ORCID,Williams Andrew¹⁶^ORCID,Celmeli Fatih¹⁷^ORCID,Hatipoglu Nevin¹⁸^ORCID,Ozcelik Tayfun¹⁹^ORCID,Picard Capucine²⁰²¹²²²³^ORCID,Abel Laurent¹²³^ORCID,Tangye Stuart G.⁴⁵^ORCID,Boisson-Dupuis Stéphanie¹²³^ORCID,Zhang Qian¹²³^ORCID,Puel Anne¹²³^ORCID,Béziat Vivien¹²³^ORCID,Casanova Jean-Laurent¹²³²⁴^ORCID,Boisson Bertrand¹²³^ORCID

Affiliation:

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

2. Paris University, Imagine Institute, Paris, France

3. Laboratory of Human Genetics of Infectious Disease, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Paris, France

4. Garvan Institute of Medical Research, Darlinghurst, Australia

5. St. Vincent’s Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia

6. Division of Basic and Clinical Immunology, Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA

7. Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

8. Genetics Unit, Military Hospital Mohamed V, Rabat, Morocco

9. Laboratory of Clinical Immunology, Inflammation and Allergy, Faculty of Medicine and Pharmacy of Casablanca, King Hassan II University, Casablanca, Morocco

10. Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Children’s Hospital, Averroes University Hospital Center, Casablanca, Morocco

11. Research Branch, Sidra Medicine, Qatar Foundation, Doha, Qatar

12. College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar

13. Department of Clinical Immunology, PathWest Laboratory Medicine Western Australia, Fiona Stanley Hospital, Perth, Australia

14. Queensland Children’s Hospital, South Brisbane, Australia

15. Department of Clinical Immunology, Princess Alexandra Hospital, Brisbane, Australia

16. Immunology Laboratory, Children’s Hospital Westmead, Westmead, Australia

17. Department of Allergy and Immunology, University of Medical Science Antalya Education and Research Hospital, Antalya, Turkey

18. Bakirkoy Dr Sadi Konuk Education and Training Hospital, Istanbul, Turkey

19. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey

20. Université de Paris, Paris, France

21. Study Center for Primary Immunodeficiencies, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France

22. Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Institut National de la Santé et de la Recherche Médicale UMR 1163, Imagine Institute, Paris, France

23. Pediatric Immunology-Hematology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France

24. Howard Hughes Medical Institute, New York, NY

Abstract

Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.

Funder

Job Research Foundation

National Center for Research Resources

National Center for Advancing Sciences

National Institutes of Health

National Institute of Allergy and Infectious Diseases

National Research Agency

Foundation for Medical Research

Howard Hughes Medical Institute

The Rockefeller University

St. Giles Foundation

Institut National de la Santé et de la Recherche Médicale