1. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation–polyendocrinopathy–enteropathy–X-linked–like syndrome
- Author
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Uzel, Gulbu, Sampaio, Elizabeth P, Lawrence, Monica G, Hsu, Amy P, Hackett, Mary, Dorsey, Morna J, Noel, Richard J, Verbsky, James W, Freeman, Alexandra F, Janssen, Erin, Bonilla, Francisco A, Pechacek, Joseph, Chandrasekaran, Prabha, Browne, Sarah K, Agharahimi, Anahita, Gharib, Ahmed M, Mannurita, Sara C, Yim, Jae Joon, Gambineri, Eleonora, Torgerson, Troy, Tran, Dat Q, Milner, Joshua D, and Holland, Steven M
- Subjects
Clinical Research ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,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 ,Immunology ,Allergy - Abstract
BackgroundMutations 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.ObjectiveWe sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.MethodsWe 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.ResultsWe 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.ConclusionsGain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
- Published
- 2013