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

Vivien Beziat; Simon Tavernier; Yin-Huai Chen; Cindy Ma; Marie Materna; Arian Laurence; Jens Staal; Dominik Aschenbrenner; Lisa Roels; Lisa Worley; Kathleen Claes; Lisa Gartner; Lisa Kohn; Marieke de Bruyne; Klaus Schmitz-Abe; Louis-Marie Charbonnier; Sevgi Keles; Justine Nammour; Natasha Vladikine; Majistor Raj Luxman Maglorius Renkilaraj; Yoann Seeleuthner; Mélanie Migaud; Jeremie Rosain; Mohamed Jeljeli; Bertrand Boisson; Eva van Braeckel; Jill A. Rosenfeld; Hongzheng Dai; Lindsay Burrage; David Murdock; Bart Lambrecht; Véronique Avettand-Fenoël; Tiphanie Vogel; Charles Esther; Sule Haskologlu; Figen Dogu; Peter Ciznar; David Boutboul; Marie Ouachée-Chardin; Jean Amourette; Marie-Noëlle Lebras; Clément Gauvain; Colas Tcherakian; Aydan Ikinciogullari; Rudi Beyaert; Laurent Abel; Joshua Milner; Bodo Grimbacher; Louis-Jean Couderc; Manish Butte; Alexandra Freeman; Emilie Catherinot; Claire Fieschi; Talal Chatila; Stuart G. Tangye; Holm Uhlig; Filomeen Haerynck; Jean-Laurent Casanova; Anne Puel

doi:10.1084/jem.20191804

Journal Articles Journal of Experimental Medicine Year : 2020

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

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Vivien Beziat

Function : Author

St. Giles Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

Laboratory of Human Genetics of Infectious Diseases

Simon Tavernier

Function : Author
PersonId : 795643
ORCID : 0000-0003-2514-5655

Ghent University Hospital

VIB-UGent Center for Inflammation Research [Gand, Belgique]

Center for Medical Genetics [Ghent]

Yin-Huai Chen

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

University of Oxford [Oxford]

Cindy Ma

Function : Author
PersonId : 794453
ORCID : 0000-0001-5387-8413

Garvan Institute of medical research

St. Vincent’s Clinical School, Faculty of Medicine

Marie Materna

Function : Author
PersonId : 800325
ORCID : 0000-0003-1180-6651

Imagine - Institut des maladies génétiques (IHU)

Laboratory of Human Genetics of Infectious Diseases

Arian Laurence

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

University of Oxford [Oxford]

Jens Staal

Function : Author

VIB-UGent Center for Inflammation Research [Gand, Belgique]

Dominik Aschenbrenner

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

University of Oxford [Oxford]

Lisa Roels

Function : Author

Ghent University Hospital

Center for Medical Genetics [Ghent]

Lisa Worley

Function : Author

Garvan Institute of medical research

St. Vincent’s Clinical School, Faculty of Medicine

Kathleen Claes

Function : Author
PersonId : 791343
ORCID : 0000-0003-0841-7372

Ghent University Hospital

Center for Medical Genetics [Ghent]

Lisa Gartner

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

University of Oxford [Oxford]

Lisa Kohn

Function : Author

University of California

Marieke de Bruyne

Function : Author

Center for Medical Genetics [Ghent]

Ghent University Hospital

Klaus Schmitz-Abe

Function : Author

Boston Children's Hospital

Harvard Medical School [Boston]

Louis-Marie Charbonnier

Function : Author
PersonId : 765174
ORCID : 0000-0002-4594-7893

Harvard Medical School [Boston]

Boston Children's Hospital

Sevgi Keles

Function : Author
PersonId : 779159
ORCID : 0000-0001-7344-8947

Necmettin Erbakan University [Konya, Turquie]

Justine Nammour

Function : Author

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

Natasha Vladikine

Function : Author

Imagine - Institut des maladies génétiques (IHU)

Laboratory of Human Genetics of Infectious Diseases

Majistor Raj Luxman Maglorius Renkilaraj

Function : Author
PersonId : 782741
ORCID : 0000-0002-8385-2860

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

Yoann Seeleuthner

Function : Author
PersonId : 779912
ORCID : 0000-0002-1878-8567

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

Mélanie Migaud

Function : Author
PersonId : 769678
ORCID : 0000-0003-3062-1214

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

Jeremie Rosain

Function : Author

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

Mohamed Jeljeli

Function : Author

Hôpital Cochin [AP-HP]

Bertrand Boisson

Function : Author
PersonId : 757762
ORCID : 0000-0001-5240-3555
IdRef : 08188317X

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

St. Giles Laboratory of Human Genetics of Infectious Diseases

Eva van Braeckel

Function : Author

Ghent University Hospital

Jill A. Rosenfeld

Function : Author
PersonId : 906001

Baylor College of Medicine

Hongzheng Dai

Function : Author

Baylor College of Medicine

Lindsay Burrage

Function : Author

Baylor College of Medicine

David Murdock

Function : Author

Baylor College of Medicine

Bart Lambrecht

Function : Author

VIB-UGent Center for Inflammation Research [Gand, Belgique]

Ghent University Hospital

Véronique Avettand-Fenoël

Function : Author
PersonId : 765802
ORCID : 0000-0002-7022-2990
IdRef : 09320955X

Laboratoire de Virologie [CHU Necker]

Tiphanie Vogel

Function : Author

Baylor College of Medicine

Charles Esther

Function : Author

University of North Carolina [Chapel Hill]

Sule Haskologlu

Function : Author
PersonId : 800326
ORCID : 0000-0002-2668-0441

Ankara University School of Medicine [Turkey]

Figen Dogu

Function : Author
PersonId : 779161
ORCID : 0000-0002-7869-4941

Ankara University School of Medicine [Turkey]

Peter Ciznar

Function : Author

Comenius University in Bratislava

David Boutboul

Function : Author

Service d'Immunopathologie [Hôpital Saint-Louis, Paris]

Marie Ouachée-Chardin

Function : Author

Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris]

Jean Amourette

Function : Author

Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras

Marie-Noëlle Lebras

Function : Author

Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris]

Clément Gauvain

Function : Author

Colas Tcherakian

Function : Author

Service de pneumologie [Hôpital Foch]

Aydan Ikinciogullari

Function : Author
PersonId : 779160
ORCID : 0000-0003-1145-0843

Ankara University School of Medicine [Turkey]

Rudi Beyaert

Function : Author
PersonId : 883571

VIB-UGent Center for Inflammation Research [Gand, Belgique]

Laurent Abel

Function : Author
PersonId : 756191
ORCID : 0000-0001-7016-6493
IdRef : 07779432X

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

St. Giles Laboratory of Human Genetics of Infectious Diseases

Joshua Milner

Function : Author
PersonId : 800327
ORCID : 0000-0002-3913-3869

National Institute of Allergy and Infectious Diseases [Bethesda]

Columbia University Irving Medical Center

Bodo Grimbacher

Function : Author

Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany

Centre for Integrative Biological Signaling Studies [Freiburg, Germany]

Hanover Medical School

Louis-Jean Couderc

Function : Author
PersonId : 915368

Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique

Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil

Service de pneumologie [Hôpital Foch]

Manish Butte

Function : Author

Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles

Alexandra Freeman

Function : Author

National Institute of Allergy and Infectious Diseases [Bethesda]

Emilie Catherinot

Function : Author

Service de pneumologie [Hôpital Foch]

Claire Fieschi

Function : Author

Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)

Hopital Saint-Louis [AP-HP]

Talal Chatila

Function : Author

Harvard Medical School [Boston]

Boston Children's Hospital

Stuart G. Tangye

Function : Author

Garvan Institute of medical research

St. Vincent’s Clinical School [Sydney, Australia]

Holm Uhlig

Function : Author

John Radcliffe Hospital [Oxford University Hospital]

University of Oxford [Oxford]

Filomeen Haerynck

Function : Author
PersonId : 892234

Ghent University Hospital

Jean-Laurent Casanova

Function : Author
PersonId : 756193
ORCID : 0000-0002-7782-4169
IdRef : 073388726

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

St. Giles Laboratory of Human Genetics of Infectious Diseases

CHU Necker - Enfants Malades [AP-HP]

Anne Puel

Function : Author
PersonId : 757898
ORCID : 0000-0003-2603-0323
IdRef : 170297969

Laboratory of Human Genetics of Infectious Diseases

Imagine - Institut des maladies génétiques (IHU)

St. Giles Laboratory of Human Genetics of Infectious Diseases

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

Domains

Life Sciences [q-bio] Immunology

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Submitted on : Tuesday, April 21, 2020-3:31:27 PM

Last modification on : Tuesday, November 29, 2022-11:56:14 AM

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hal-02549533 , version 1 (21-04-2020)

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HAL Id : hal-02549533 , version 1
DOI : 10.1084/jem.20191804
PUBMEDCENTRAL : PMC7971136

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Vivien Beziat, Simon Tavernier, Yin-Huai Chen, Cindy Ma, Marie Materna, et al.. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. Journal of Experimental Medicine, 2020, 217 (6), ⟨10.1084/jem.20191804⟩. ⟨hal-02549533⟩

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

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