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Blood. 2015 Jan 22;125(4):591-9. doi: 10.1182/blood-2014-09-602763. Epub 2014 Oct 30.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Author information

1
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
2
Departments of Pediatrics, Division of Rheumatology, and Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO;
3
Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Center for Human Immunobiology of Texas Children's Hospital, and.
4
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;
5
Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD;
6
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
7
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
8
Departments of Pediatrics, Division of Rheumatology, and.
9
Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO; Department of Genetics, Washington University School of Medicine, St. Louis, MO;
10
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
11
Departments of Pediatrics, Division of Rheumatology, Microbiology and Medical Genetics, and.
12
Departments of Pediatrics, Division of Rheumatology, Microbiology and Medical Genetics, and Clinical Immunodiagnostic & Research Laboratory, Medical College of Wisconsin, Milwaukee, WI;
13
Departments of Pediatrics, Section of Immunology, Allergy, and Rheumatology.
14
Department of Pediatrics, Baylor College of Medicine, Houston, TX;
15
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;
16
Department of Pediatrics, Oslo University Hospital, Oslo, Norway;
17
Merck Research Laboratories, Boston, MA;
18
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
19
Department of Pediatrics, Section of Pediatric Gastroenterology and.
20
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;
21
Departments of Pediatrics, Division of Allergy and Immunology, and.
22
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;
23
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.
24
Departments of Pediatrics, Division of Rheumatology, and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

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.

PMID:
25359994
PMCID:
PMC4304103
DOI:
10.1182/blood-2014-09-602763
[Indexed for MEDLINE]
Free PMC Article

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