title: Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.
abstract: The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.
authors.affiliation: Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology, and.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Haapaniemi
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Meri
authors.initials: M
authors.lastname: Kaustio
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;
authors.forename: Hanna L M
authors.initials: HL
authors.lastname: Rajala
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: van Adrichem
authors.affiliation: Department of Pediatrics and Department of Medicine, Turku University Hospital, Turku, Finland;
authors.forename: Leena
authors.initials: L
authors.lastname: Kainulainen
authors.affiliation: Department of Medical Microbiology and Immunology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland;
authors.forename: Virpi
authors.initials: V
authors.lastname: Glumoff
authors.affiliation: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital and National Institute for Health Research, Cambridge Biomedical Research Center, Cambridge, United Kingdom;
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Heikki
authors.initials: H
authors.lastname: Kuusanmäki
authors.affiliation: Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland;
authors.forename: Tarja
authors.initials: T
authors.lastname: Heiskanen-Kosma
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Luca
authors.initials: L
authors.lastname: Trotta
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Samuel
authors.initials: S
authors.lastname: Chiang
authors.affiliation: Department of Medical Microbiology and Immunology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Pediatrics, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland;
authors.forename: Petri
authors.initials: P
authors.lastname: Kulmala
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Samuli
authors.initials: S
authors.lastname: Eldfors
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, University of Helsinki, Helsinki, Finland;
authors.forename: Riku
authors.initials: R
authors.lastname: Katainen
authors.affiliation: Laboratory Services (Hospital District of Helsinki and Uusimaa Laboratory).
authors.forename: Sanna
authors.initials: S
authors.lastname: Siitonen
authors.affiliation: Laboratory Services (Hospital District of Helsinki and Uusimaa Laboratory).
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Karjalainen-Lindsberg
authors.affiliation: Department of Pathology, and.
authors.forename: Panu E
authors.initials: PE
authors.lastname: Kovanen
authors.affiliation: Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland;
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Kaarina
authors.initials: K
authors.lastname: Heiskanen
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland;
authors.forename: Arno
authors.initials: A
authors.lastname: Hänninen
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.affiliation: Department of Infectious Diseases, Satakunta Central Hospital, Pori, Finland;
authors.forename: Raija
authors.initials: R
authors.lastname: Uusitalo-Seppälä
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.affiliation: Immunodeficiency Unit, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; and.
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppänen
authors.affiliation: Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland;
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.affiliation: Folkhälsan Institute of Genetics and Research Programs Unit, Molecular Neurology, and Department of Biosciences and Nutrition, and Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
mesh_terms: D000293:Adolescent; D000328:Adult; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019943:Amino Acid Substitution; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020125:Mutation, Missense; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human