Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.
| Title: | Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. |
|---|---|
| Authors: | Béziat V; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.; Tavernier SJ; 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.; VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Ghent, Belgium.; Chen YH; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.; Ma CS; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; St. Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.; Materna M; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Laurence A; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.; Staal J; VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Ghent, Belgium.; Aschenbrenner D; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.; Roels L; 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.; Worley L; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; St. Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.; Claes K; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.; Gartner L; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.; Kohn LA; Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA.; De Bruyne M; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.; Schmitz-Abe K; Division of Newborn Medicine and Neonatal Genomics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA.; Charbonnier LM; Department of Pediatrics, Harvard Medical School, Boston, MA.; Division of Immunology, Boston Children's Hospital, Boston, MA.; Keles S; Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey.; Nammour J; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Vladikine N; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Maglorius Renkilaraj MRL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Seeleuthner Y; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Migaud M; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Rosain J; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; Jeljeli M; Cochin University Hospital, Biological Immunology Unit, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.; Boisson B; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.; Van Braeckel E; Department of Respiratory Medicine, Ghent University Hospital, Ghent Belgium.; Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Dai H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Murdock DR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Lambrecht BN; VIB-UGent Center for Inflammation Research, Unit of Immunoregulation and Mucosal Immunology, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.; Avettand-Fenoel V; Laboratory of Clinical Microbiology, Virology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.; Vogel TP; Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.; Esther CR; Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC.; Haskologlu S; Division of Pediatric Immunology and Allergy, Ankara University School of Medicine, Sıhhıye, Ankara, Turkey.; Dogu F; Division of Pediatric Immunology and Allergy, Ankara University School of Medicine, Sıhhıye, Ankara, Turkey.; Ciznar P; Department of Pediatrics, Faculty of Medicine Comenius University and Children's University Hospital, Bratislava, Slovakia.; Boutboul D; Clinical Immunology Department, Saint Louis Hospital, AP-HP de Paris University of Paris, Paris, France.; Ouachée-Chardin M; Department of Pediatric Hematology and Immunology, Robert Debré Hospital, AP-HP, Paris, France.; Amourette J; Pulmonology Department, Centre Hospitalier d'Arras, Arras, France.; Lebras MN; Pediatric Pulmonology, Infectious Disease and Internal Medicine Department, AP-HP, Robert Debré Hospital, Paris, France.; Gauvain C; Thoracic Oncology Department, Lille University Hospital, Lille, France.; Tcherakian C; Hôpital Foch, Pulmonology Department, Suresnes, France.; Ikinciogullari A; Division of Pediatric Immunology and Allergy, Ankara University School of Medicine, Sıhhıye, Ankara, Turkey.; Beyaert R; VIB-UGent Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Ghent, Belgium.; Abel L; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.; Milner JD; National Institute of Allergy and Infectious Diseases, Bethesda, MD.; Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY.; Grimbacher B; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.; German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany.; Centre for Integrative Biological Signaling Studies, Albert Ludwig University, Freiburg, Germany.; RESIST, Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany.; Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK.; Couderc LJ; Hôpital Foch, Pulmonology Department, Suresnes, France.; Simone Veil Faculty of Life Sciences, Versailles-Paris Saclay University, UPRES EA-220, Suresnes, France.; Butte MJ; Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA.; Freeman AF; National Institute of Allergy and Infectious Diseases, Bethesda, MD.; Catherinot É; Hôpital Foch, Pulmonology Department, Suresnes, France.; Fieschi C; Clinical Immunology Department, Saint Louis Hospital, AP-HP de Paris University of Paris, Paris, France.; INSERM UMR1126, Institut de Recherche Saint-Louis, Université de Paris, Paris, France.; Chatila TA; Department of Pediatrics, Harvard Medical School, Boston, MA.; Division of Immunology, Boston Children's Hospital, Boston, MA.; Tangye SG; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; St. Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.; Uhlig HH; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.; Haerynck F; 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.; Department of Internal Medicine and Pediatrics, Division of Pediatric Immunology and Pulmonology, Ghent University Hospital, Ghent, Belgium.; Casanova JL; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.; Howard Hughes Medical Institute, New York, NY.; Puel A; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.; University of Paris, Imagine Institute, Paris, France.; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY. |
| Corporate Authors: | Undiagnosed Diseases Network |
| Source: | The Journal of experimental medicine [J Exp Med] 2020 Jun 01; Vol. 217 (6). |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985109R Publication Model: Print Cited Medium: Internet ISSN: 1540-9538 (Electronic) Linking ISSN: 00221007 NLM ISO Abbreviation: J Exp Med Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York, NY : Rockefeller University Press |
| MeSH Terms: | Genes, Dominant*; Cytokine Receptor gp130/*genetics ; Job Syndrome/*genetics ; Mutation/*genetics; C-Reactive Protein/metabolism ; Cell Membrane/metabolism ; Cytokine Receptor gp130/deficiency ; Cytokines/biosynthesis ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Job Syndrome/blood ; Job Syndrome/diagnostic imaging ; Job Syndrome/immunology ; Loss of Function Mutation/genetics ; Th2 Cells/metabolism ; Adolescent ; Alleles ; Cells, Cultured ; Child ; Female ; Genetics, Population ; HEK293 Cells ; Humans ; Kinetics ; Male ; Middle Aged ; Models, Biological ; Pedigree ; Phenotype ; Up-Regulation ; Young Adult |
| 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.; (© 2020 Béziat et al.) |
| Competing Interests: | Disclosures: Dr. Chen reported grants from Bristol-Myers Squibb during the conduct of the study. Dr. Rosenfeld reported personal fees from Baylor Genetics Laboratories outside the submitted work. Dr. Milner reported a patent to use STAT3 inhibition to prevent anaphylaxis pending. Dr. Couderc reported non-financial support from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Novartis, and grants from LVL outside the submitted work. Dr. Catherinot reported financial support for travel and registration expenses related to international medical meetings (LVL Medical, CSL Behring). Dr. Uhlig reported grants from Celgene during the conduct of the study and grants from UCB and Eli Lilly outside the submitted work. Dr. Haerynck reported, "Centre for Primary Immune deficiency is recognized as a Jeffrey Modell Foundation diagnostic and research center and supported by the Jeffrey Modell Foundation; the University Hospital Ghent Spearhead Initiative for Immunology Research (until 7/2019); the Grand Challenges Program of VIB (this VIB Program received support from the Flemish Government under the Management Agreement 2017-2021; VR 2016 2312 Doc.1521/4); Simon Tavernier is a postdoctoral fellow at PID research lab with the Fund for Scientific Research Flanders (FWO, 12W9119N); I am funded by a university research grant (BOF-University Ghent)." No other disclosures were reported. |
| Comments: | Erratum in: J Exp Med. 2020 Jun 1;217(7):e2019180405272020c. doi: 10.1084/jem.2019180405272020c.. (PMID: 32516385) |
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| Grant Information: | R01 AI128976 United States AI NIAID NIH HHS; UM1 HG006504 United States HG NHGRI NIH HHS; R01 AI085090 United States AI NIAID NIH HHS; U01 HG007709 United States HG NHGRI NIH HHS; P01 AI061093 United States AI NIAID NIH HHS; R01 AI127564 United States AI NIAID NIH HHS; U24 HG008956 United States HG NHGRI NIH HHS; United States HHMI Howard Hughes Medical Institute; UL1 TR001866 United States TR NCATS NIH HHS |
| Substance Nomenclature: | 0 (Cytokines); 0 (IL6ST protein, human); 133483-10-0 (Cytokine Receptor gp130); 9007-41-4 (C-Reactive Protein) |
| Entry Date(s): | Date Created: 20200325 Date Completed: 20210216 Latest Revision: 20260405 |
| Update Code: | 20260405 |
| PubMed Central ID: | PMC7971136 |
| DOI: | 10.1084/jem.20191804 |
| PMID: | 32207811 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't