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. doi: 10.1016/j.jaci.2012.11.054. Epub 2013 Mar 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Autoantibodies / immunology
  • Cell Line, Transformed
  • Child
  • Child, Preschool
  • DNA / metabolism
  • Female
  • Forkhead Transcription Factors / genetics*
  • Genes, Dominant*
  • Genetic Diseases, X-Linked / diagnosis
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / immunology
  • Humans
  • Immunophenotyping
  • Interferon-alpha / immunology
  • Interferon-gamma / pharmacology
  • Interleukin-17 / immunology
  • Interleukin-22
  • Interleukins / immunology
  • Intestinal Diseases / diagnosis
  • Intestinal Diseases / genetics*
  • Intestinal Diseases / immunology
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Male
  • Mutation*
  • Phenotype
  • Phosphorylation / drug effects
  • Polyendocrinopathies, Autoimmune / diagnosis
  • Polyendocrinopathies, Autoimmune / genetics*
  • Polyendocrinopathies, Autoimmune / immunology
  • STAT1 Transcription Factor / genetics*
  • STAT1 Transcription Factor / metabolism
  • Syndrome
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Transcriptional Activation

Substances

  • Autoantibodies
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interferon-alpha
  • Interleukin-17
  • Interleukins
  • STAT1 Transcription Factor
  • Interferon-gamma
  • DNA