Faculty Collaboration Database

Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol 2013 Jun;131(6):1611-23

Date

03/29/2013

Pubmed ID

23534974

Pubmed Central ID

PMC3672257

DOI

10.1016/j.jaci.2012.11.054

Scopus ID

2-s2.0-84878556463 (requires institutional sign-in at Scopus site)   248 Citations

Abstract

BACKGROUND: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.

OBJECTIVE: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.

METHODS: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.

RESULTS: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.

CONCLUSIONS: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.

Author List

Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, Noel RJ, Verbsky JW, Freeman AF, Janssen E, Bonilla FA, Pechacek J, Chandrasekaran P, Browne SK, Agharahimi A, Gharib AM, Mannurita SC, Yim JJ, Gambineri E, Torgerson T, Tran DQ, Milner JD, Holland SM

Author

James Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Autoantibodies
Cell Line, Transformed
Child
Child, Preschool
DNA
Female
Forkhead Transcription Factors
Genes, Dominant
Genetic Diseases, X-Linked
Humans
Immunophenotyping
Interferon-alpha
Interferon-gamma
Interleukin-17
Interleukins
Intestinal Diseases
Lymphocyte Subsets
Male
Mutation
Phenotype
Phosphorylation
Polyendocrinopathies, Autoimmune
STAT1 Transcription Factor
Syndrome
T-Lymphocytes, Regulatory
Th17 Cells
Transcriptional Activation