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Sci Immunol. 2018 Jun 15;3(24). pii: eaat4941. doi: 10.1126/sciimmunol.aat4941.

ZNF341 controls STAT3 expression and thereby immunocompetence.

Author information

1
Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
2
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
3
Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
4
Department of Pediatrics, Hillel Yaffe Medical Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
5
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20894, USA.
6
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
7
Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.
8
Allergy and Immunology Clinic, Meir Medical Center, Kfar Saba, Israel.
9
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.
10
Paris Descartes University, Imagine Institute, 75015 Paris, France.
11
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
12
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Assistance Publique des Hôpitaux de Paris, 75015 Paris, France.
13
Howard Hughes Medical Institute, New York, NY 10065, USA.
14
Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, Erlangen, Germany.
15
Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
16
Department of Pediatric Immunology, Uludag University Medical Faculty, Gorukle-Bursa, Turkey.
17
Allergy and Immunology Clinic, Schneider Children's Medical Center, Tel Aviv, Israel.
18
Ruth's Children Hospital, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
19
Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. bodo.grimbacher@uniklinik-freiburg.de.
20
Institute of Immunology and Transplantation, Royal Free Hospital and University College London, London, UK.
21
DZIF (German Center for Infection Research) Satellite Center Freiburg, Germany.

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

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