Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Karin Engelhardt, Dr David Swan, Dr Yaobo Xu, Dr Mauro Santibanez Koref, Professor Andrew Cant, Professor Sophie HambletonORCiD


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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, germlinemutations 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, withmost 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 as #NCT00001350.

Publication metadata

Author(s): Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson EDO, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, Perminow G, Rao VK, O'Connell MP, Price S, Su HC, Butrick M, McElwee J, Hughes JD, Willet J, Swan D, Xu Y, Santibanez-Koref M, Slowik V, Dinwiddie DL, Ciaccio CE, Saunders CJ, Septer S, Kingsmore SF, White AJ, Cant AJ, Hambleton S, Cooper MA

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2015

Volume: 125

Issue: 4

Pages: 591-599

Print publication date: 22/01/2015

Acceptance date: 27/10/2014

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology


DOI: 10.1182/blood-2014-09-602763


Altmetrics provided by Altmetric


Funder referenceFunder name
Marion Merrell Dow Foundation
NIH Roadmap for Medical Research
Pat and Gil Clements Foundation
St. Louis Children's Hospital
Black Veatch
Children's Discovery Institute
Claire Giannini Foundation
National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
Scleroderma Foundation
Sir Jules Thorn Charitable Trust
WT Kemper Foundation
P30 CA91842National Cancer Institute (NCI) Cancer Center
P30AR048335National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
P30AR048335Rheumatic Diseases Core Center at Washington University
U19HD077693National Institute of Child Health and Human Development (NICHD)
U54HG003273NIH National Human Genome Research Institute
U54HG006542NIH National Human Genome Research Institute
UL1TR000448Institute of Clinical and Translational Sciences/Clinical & Translational Science Awards (ICTS/CTSA) from the National Center for Research Resources, a component of the NIH