Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome

Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 03/2013; 131(6). DOI: 10.1016/j.jaci.2012.11.054
Source: PubMed


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.

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    • "Patients with this disease suffer from both severe viral infections (herpes viruses), as well as intracellular pathogens (Salmonella, BCG, and nontuberculous mycobacteria).12 Interestingly, gain of function autosomal dominant STAT1 mutations can develop infections similar to those with loss of function mutations but can also develop infections with dimorphic molds (Samplaio et al.13) as well as CMC and autoimmunity (Uzel et al.14). Although these patients have increased expression of cytokines that promote Th17 immune deviation (IL-6 and IL-21), ultimately, the stronger cellular responses to the STAT-1 activating cytokines IFN-α/β, IFN-γ, and IL-27 prevail, and their Th1 immune deviating influences supersede and hinder the development of Th17 cells.15 "
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    ABSTRACT: As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll-like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral‐esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward.
    Full-text · Article · Oct 2014 · Allergy and Asthma Proceedings
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    • "Additionally some children have a susceptibility to mycobacteria and they may have antibody deficiency or a hyper-IgM syndrome. Some mutations in the transcription factor, STAT-1, alter signaling of cytokines including that of IFNgamma , IL-6, and IL-21 reduce IL-17 producing T cells and can cause CMCC, recurrent viral infections, enteropathy , mycobacterial infections, and multiple endocrine autoimmunity (Uzel et al. 2013). These patients can have elevated immunoglobulins with poor antibody production among other immune abnormalities such as lymphopenia. "

    Full-text · Article · Sep 2014
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    • "Sampaio et al. recently detected the STAT1-F172L mutation in a 25-year-old woman with recurrent oral, cutaneous, and vaginal candidiasis and a history of disseminated histoplasmosis [14]. These authors also reported on a T385M substitution in two patients with FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome [15]. "
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    ABSTRACT: A transition from a parallel to an antiparallel dimer configuration of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for interferon (IFN)-mediated signal transduction. However, the precise molecular mechanisms linking conformational changes to target gene activation by STAT1 are still largely unknown. In the present study, we have characterized, in more detail than before, two disease-associated point mutants with amino acid substitutions at both sites of the dimer interface (F172W and T385A). First, we confirmed that IFNγ-stimulation of transfected cells led to enhanced tyrosine phosphorylation of mutant STAT1 as compared to the wild-type protein, which consequently resulted in its prolonged nuclear accumulation. Using an in vitro dephosphorylation assay, we demonstrated that, in contrast to wild-type STAT1 and similar to the F172W mutant, also T385A resisted enzymatic inactivation by the nuclear phosphatase Tc45. Transcriptional activation of IFNγ-driven endogenous target genes differed between wild-type and mutant STAT1. While expression of genes containing a single classical gamma-activated site (GAS), such as irf1, gpb1, and mig1, was virtually unaffected by the presence of either of two amino acid exchanges, induction of the cxcl10 and mcp1 gene was significantly enhanced. The latter two genes both contain an additional TTC/GAA binding motif separated by 10 bp from the palindromic GAS sequence. The transcriptional superiority of the mutants on these genes was reflected by their increased binding affinity to DNA fragments containing the identified "one-and-a-half-GAS" motif. In summary, our data demonstrate that two clinically relevant interface mutants of STAT1 exhibit gene-specific effects and point to the rather complex role of the assumed conformational shift between two different dimer configurations for efficient transcriptional regulation.
    Preview · Article · Jul 2013 · PLoS ONE
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