title: Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.
abstract: Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.affiliation: Departments of Pediatrics, Division of Rheumatology, and Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO;
authors.forename: Tiphanie P
authors.initials: TP
authors.lastname: Vogel
authors.affiliation: Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Forbes
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.affiliation: Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and Molecular and Human Genetics, Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD;
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyons
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Karin R
authors.initials: KR
authors.lastname: Engelhardt
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departments of Pediatrics, Division of Rheumatology, and.
authors.forename: Nermina
authors.initials: N
authors.lastname: Topcagic
authors.affiliation: Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO; Department of Genetics, Washington University School of Medicine, St. Louis, MO;
authors.forename: Elisha D O
authors.initials: ED
authors.lastname: Roberson
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Helen
authors.initials: H
authors.lastname: Matthews
authors.affiliation: Departments of Pediatrics, Division of Rheumatology, Microbiology and Medical Genetics, and.
authors.forename: James W
authors.initials: JW
authors.lastname: Verbsky
authors.affiliation: Departments of Pediatrics, Division of Rheumatology, Microbiology and Medical Genetics, and Clinical Immunodiagnostic & Research Laboratory, Medical College of Wisconsin, Milwaukee, WI;
authors.forename: Trivikram
authors.initials: T
authors.lastname: Dasu
authors.affiliation: Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vargas-Hernandez
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX;
authors.forename: Nidhy
authors.initials: N
authors.lastname: Varghese
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX;
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: McClain
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX;
authors.forename: Lina B
authors.initials: LB
authors.lastname: Karam
authors.affiliation: Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
authors.forename: Karen
authors.initials: K
authors.lastname: Nahmod
authors.affiliation: Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
authors.forename: George
authors.initials: G
authors.lastname: Makedonas
authors.affiliation: Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;
authors.forename: Hanne S
authors.initials: HS
authors.lastname: Sorte
authors.affiliation: Department of Pediatrics, Oslo University Hospital, Oslo, Norway;
authors.forename: Gøri
authors.initials: G
authors.lastname: Perminow
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Morgan
authors.initials: M
authors.lastname: Butrick
authors.affiliation: Merck Research Laboratories, Boston, MA;
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.affiliation: Merck Research Laboratories, Boston, MA;
authors.forename: Jason D
authors.initials: JD
authors.lastname: Hughes
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Joseph
authors.initials: J
authors.lastname: Willet
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Swan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Yaobo
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: Department of Pediatrics, Section of Pediatric Gastroenterology and.
authors.forename: Voytek
authors.initials: V
authors.lastname: Slowik
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO; Department of Pediatrics and Clinical Translational Science Center, University of New Mexico Health Sciences Center, Albuquerque, NM;
authors.forename: Darrell L
authors.initials: DL
authors.lastname: Dinwiddie
authors.affiliation: Departments of Pediatrics, Division of Allergy and Immunology, and.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Ciaccio
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO; Pathology, Children's Mercy Hospital and Clinics Kansas City, MO; School of Medicine, University of Missouri-Kansas City, Kansas City, MO;
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Saunders
authors.affiliation: Department of Pediatrics, Section of Pediatric Gastroenterology and.
authors.forename: Seth
authors.initials: S
authors.lastname: Septer
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Kansas City, MO; Pathology, Children's Mercy Hospital and Clinics Kansas City, MO; School of Medicine, University of Missouri-Kansas City, Kansas City, MO;
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.affiliation: Departments of Pediatrics, Division of Rheumatology, and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: White
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Paediatric Immunology and Infectious Diseases, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Paediatric Immunology and Infectious Diseases, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.affiliation: Departments of Pediatrics, Division of Rheumatology, and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor