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Sci Immunol. 2018 Jun 15;3(24). pii: eaat4956. doi: 10.1126/sciimmunol.aat4956.

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France. anne.puel@inserm.fr jean-laurent.casanova@rockefeller.edu vivien.beziat@inserm.fr.
2
Paris Descartes University, Imagine Institute, 75015 Paris, France.
3
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
4
Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
5
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia.
6
St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
7
Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca, Morocco.
8
Pediatric Hemato-Oncology Unit, University Hospital of Angers, 49933 Angers, France.
9
Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.
10
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran.
11
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
12
Marmara University School of Medicine, Department of Pediatrics, Division of Allergy and Immunology, 34899 Istanbul, Turkey.
13
Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, 42060 Konya, Turkey.
14
Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia.
15
School of Women's and Children's Health, University of New South Wales School of Women's and Children's Health, Sydney, New South Wales 2031, Australia.
16
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.
17
Innate Immunity Unit, Institut Pasteur, 75015 Paris, France.
18
INSERM U1223, 75015 Paris, France.
19
Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
20
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
21
Unit of Tropical and Infectious Diseases, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.
22
Sidra Medicine, Doha, Qatar.
23
INSERM-U1149, CNRS-ERL8252, Center for Research on Inflammation, Labex Inflamex, Paris Diderot University, Faculté de Médecine, Xavier Bichat Medical School, 75018 Paris, France.
24
Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
25
Department of Paediatric Dermatology, Sydney Children's Hospital, High Street, Randwick, New South Wales 2031, Australia.
26
Study Center for Immunodeficiency, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
27
Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
28
Department of Hematology, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
29
Referral Center for Immunodeficiency, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
30
Laboratory of Genetic Skin Diseases: from Disease Mechanism to Therapies, INSERM U1163, 75015 Paris, France.
31
Department of Pathology, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
32
Immunology Laboratory, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
33
Virology Laboratory, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
34
Paris Descartes University, EA 73-28, 75015 Paris, France.
35
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
36
Department of Immunology and Microbiology, Childhood Immunology, Department of Pediatrics, University Hospitals Leuven and KU Leuven, 3000 Leuven, Belgium.
37
Department of Genetics, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
38
Istanbul University, Istanbul Medical Faculty, Division of Infectious Diseases and Immunology, 34452 Istanbul, Turkey.
39
Howard Hughes Medical Institute, New York, NY 10065, USA.

Abstract

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

PMID:
29907691
PMCID:
PMC6141026
[Available on 2018-12-15]
DOI:
10.1126/sciimmunol.aat4956

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