Title

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

Document Type

Article

Publication Date

1-22-2015

Identifier

DOI: 10.1182/blood-2014-09-602763; PMCID: PMC4304103

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.

Journal Title

Blood

Volume

125

Issue

4

First Page

591

Last Page

599

MeSH Keywords

Adolescent; Adult; Autoimmune Diseases; Child; Child, Preschool; Female; Genetic Diseases, Inborn; Humans; Infant; Lymphoproliferative Disorders; Male; Mutation; Phosphorylation; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; T-Lymphocytes, Regulatory

Keywords

mutation, stat3 protein, autoimmunity

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