Identification of a new gene involved in severe allergies and eczema

An international consortium (*), including the Human Genetics of Infectious Diseases Laboratory at the Imagine Institute (Inserm, APHP, Université Paris Cité), has published a new study in the Journal of Experimental Medicine. The doctors and researchers have identified a new gene involved in the "hyper IgE" syndrome, responsible for severe allergies and eczema.  

Published on

09.03.2023

Research Acceleration

Patients with hyper IgE syndrome present with allergies, severe eczema, skin and lung infections. The syndrome was first described in 1966 in the Lancet. But it was not until about 40 years later that a genetic cause was identified. In 2007, a Japanese team highlighted the involvement of the STAT3 gene in the occurrence of this rare syndrome. "Following this work, our laboratory identified two new genes involved in this syndrome: ZNF341 and IL6ST," explains Vivien Béziat, researcher and theme leader in the Human Genetics of Infectious Diseases laboratory, directed by Professor Jean-Laurent Casanova, at the Institut Imagine.

In a new study published in the Journal of Experimental Medicine [1], a large international consortium, of which the Imagine Institute is a member, has identified mutations in the STAT6 gene, which is involved in the development of this disease. The team of Prof. Stuart Turvey, a physician and researcher at the BC Children's Hospital, University of British Columbia, Vancouver, had highlighted the involvement of this gene in two patients in an article published in MedRxiv, a scientific pre-publication platform," explains Vivien Béziat. When this information was published, we started to study two patients with a mutation in the same gene. We then contacted Prof. Turvey to inform him that we had also identified patients suffering from the same disease.

Discovery of mutations in the STAT6 gene In total, 16 patients from 10 families were included in the study. All had severe eczema resistant to treatment, food and/or drug allergies, recurrent respiratory infections, skin infections (viruses, etc.), etc.

The researchers found that the majority of these patients carried mutations that affected the same amino acid in the STAT6 protein. Strikingly, the mutations found in the patients are the same as those found in certain cancers, in particular lymphomas," explains Vivien Béziat. In the case of tumours, these mutations appear during the life of the individual (somatic mutations). However, our patients carry these mutations from birth (germline mutations), and the disease does not manifest itself as cancer, but as extremely severe allergic reactions.

Genes involved in allergy are overactivated By analysing these variants, the researchers have shown that the mutations in question are of the 'gain-of-function' type. This means that the STAT6 protein is more active than its non-mutated form. The role of STAT6 is to control the expression of genes involved in allergy, in particular that of the IL-4 receptor (IL-4R). Hence the idea of blocking the activity of this receptor in patients.

"Some patients have received dupilumab, an antibody-based treatment that blocks the activity of IL4R. These patients saw their allergic symptoms decrease significantly, dramatically improving their living conditions," says the researcher.

This study thus provides a new molecular explanation for this very disabling and even fatal disease for some patients, and offers the possibility of adapted treatments.

[1] https://doi.org/10.1084/jem.2022175

(*) The consortium :

Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China;
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France; Imagine Institute, University of Paris-Cite, Paris, France;
Dept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy;
Academic Dept. of Pediatrics (DPUO), Unit of Clinical Immunology and Vaccinology, IRCCS Bambin Gesu Children Hospital, Rome, Italy;
Research Unit of Primary Immunodeficiency, IRCCS Bambin Gesu Children Hospital, Rome, Italy;
Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA;
Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;
Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium;
Dept. of Pediatrics, Pediatric Immunodeficiencies Division, University Hospitals Leuven, Leuven, Belgium;
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK;
Dept. of Immunology, Royal Free London NHS Foundation Trust, London, UK; 14Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;
Dept. of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA;
Allergy Centre, Union Hospital, Hong Kong, China; 18Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Vancouver, Canada;
Dept. of Medical Genetics, University of British Columbia, Vancouver, Canada;
Dept. of Medical Genetics, The University of British Columbia, Vancouver, Canada;
Genome Science and Technology Program, Faculty of Science, The University of British Columbia, Vancouver, Canada;
Dept. of Pathology, Queen Mary Hospital, Hong Kong, China;
Dept. of Pathology, Emory University, Atlanta, GA, USA;
Unit of Immunology and Vaccinology, Division of General Pediatrics, Dept. of Woman, Child, and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland;
Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, Canada;
Dept. of Paediatrics, University of Toronto, Toronto, Canada; 27Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA;
Dept. of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;
Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;
Pediatrics, Division of Pediatric Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;
NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, MD, USA;
Immunology Service, Clinical Center, NIH, Bethesda, MD, USA;
Dept. of Pediatrics, University of California San Diego, La Jolla, CA, USA;
Dept. of Medicine, Divison of Dermatology, The University of Hong Kong, Hong Kong, China;
Dept. of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong, China;
Dept. of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands;
Virtus Medical, Hong Kong, China;
Pediatric Center, Vinmec Times City International General Hospital, Hanoi, Vietnam;
Pediatrics, Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, University of Medical Sciences, Tehran, Iran;
Pediatrics, Allergy and Clinical Immunology, Lorestan University of Medical Sciences, Khoramabad, Iran;
Dept. of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran;
School of Mathematics, Institute for Research in Fundamental Sciences, Tehran, Iran;
Dept. of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;
Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, Leuven, Belgium;
DPUO, Research Unit of Infectivology and Pediatrics Drugs Development, Bambino Gesu Children Hospital IRCCS, Rome, ` Italy;
Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesu Children Hospital IRCCS, Rome, Italy;
Allergy Unit, Area of Translational Research in Pediatric Specialities, Bambino Gesu Children ` ’s Hospital, IRCCS, Rome, Italy;
Dept. of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium;
Dept. of Pediatrics, Pediatric Allergy Division, University Hospitals Leuven, Leuven, Belgium;
Dept. of Pediatrics, Pediatric Pulmonology Division, AZ Sint-Jan Brugge, Brugge, Belgium;
Dept. of Pediatrics, Pediatric Pulmonology Division, University Hospitals Leuven, Leuven, Belgium;
Dept. of Pediatrics, Pediatric Gastroenterology Division, AZ Sint-Jan Brugge, Brugge, Belgium;
Genetics Program, North York General Hospital, Toronto, Canada;
Depts. of Pediatrics and Clinical Genetics, Amsterdam University Medical Centers, Amsterdam, Netherlands;
Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA;
Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, France; 57Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran;
Dept. of Immunology, Allergy and Rheumatology, Division of Primary Immunodeficiency, Vietnam National Children’s Hospital, Hanoi, Vietnam;
Faculty of Health Sciences, McMaster University, Hamilton, Canada;
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Identification of a new gene involved in severe allergies and eczema

Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada

Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China;

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France; Imagine Institute, University of Paris-Cite, Paris, France;

Dept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy;

Academic Dept. of Pediatrics (DPUO), Unit of Clinical Immunology and Vaccinology, IRCCS Bambin Gesu Children Hospital, Rome, Italy;

Research Unit of Primary Immunodeficiency, IRCCS Bambin Gesu Children Hospital, Rome, Italy;

Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA;

Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;

Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium;

Dept. of Pediatrics, Pediatric Immunodeficiencies Division, University Hospitals Leuven, Leuven, Belgium;

Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, UK;

Dept. of Immunology, Royal Free London NHS Foundation Trust, London, UK; 14Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;

Dept. of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA;

Allergy Centre, Union Hospital, Hong Kong, China; 18Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Vancouver, Canada;

Dept. of Medical Genetics, University of British Columbia, Vancouver, Canada;

Dept. of Medical Genetics, The University of British Columbia, Vancouver, Canada;

Genome Science and Technology Program, Faculty of Science, The University of British Columbia, Vancouver, Canada;

Dept. of Pathology, Queen Mary Hospital, Hong Kong, China;

Dept. of Pathology, Emory University, Atlanta, GA, USA;

Unit of Immunology and Vaccinology, Division of General Pediatrics, Dept. of Woman, Child, and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland;

Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, Canada;

Dept. of Paediatrics, University of Toronto, Toronto, Canada; 27Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA;

Dept. of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;

Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;

Pediatrics, Division of Pediatric Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;

NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, MD, USA;

Immunology Service, Clinical Center, NIH, Bethesda, MD, USA;

Dept. of Pediatrics, University of California San Diego, La Jolla, CA, USA;

Dept. of Medicine, Divison of Dermatology, The University of Hong Kong, Hong Kong, China;

Dept. of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong, China;

Dept. of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands;

Virtus Medical, Hong Kong, China;

Pediatric Center, Vinmec Times City International General Hospital, Hanoi, Vietnam;

Pediatrics, Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, University of Medical Sciences, Tehran, Iran;

Pediatrics, Allergy and Clinical Immunology, Lorestan University of Medical Sciences, Khoramabad, Iran;

Dept. of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran;

School of Mathematics, Institute for Research in Fundamental Sciences, Tehran, Iran;

Dept. of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran;

Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, Leuven, Belgium;

DPUO, Research Unit of Infectivology and Pediatrics Drugs Development, Bambino Gesu Children Hospital IRCCS, Rome, ` Italy;

Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesu Children Hospital IRCCS, Rome, Italy;

Allergy Unit, Area of Translational Research in Pediatric Specialities, Bambino Gesu Children ` ’s Hospital, IRCCS, Rome, Italy;

Dept. of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium;

Dept. of Pediatrics, Pediatric Allergy Division, University Hospitals Leuven, Leuven, Belgium;

Dept. of Pediatrics, Pediatric Pulmonology Division, AZ Sint-Jan Brugge, Brugge, Belgium;

Dept. of Pediatrics, Pediatric Pulmonology Division, University Hospitals Leuven, Leuven, Belgium;

Dept. of Pediatrics, Pediatric Gastroenterology Division, AZ Sint-Jan Brugge, Brugge, Belgium;

Genetics Program, North York General Hospital, Toronto, Canada;

Depts. of Pediatrics and Clinical Genetics, Amsterdam University Medical Centers, Amsterdam, Netherlands;

Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA;

Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, France; 57Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran;

Dept. of Immunology, Allergy and Rheumatology, Division of Primary Immunodeficiency, Vietnam National Children’s Hospital, Hanoi, Vietnam;

Faculty of Health Sciences, McMaster University, Hamilton, Canada;

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