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

• Published in: Journal of allergy and clinical immunology Vol. 131; no. 6; pp. 1611 - 1623.e3
• Main Authors: 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., Holland, Steven M.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.06.2013; Elsevier
• Subjects: Adolescent; alleles; Allergy and Immunology; aneurysms; Autoantibodies - immunology; autoimmunity; Biological and medical sciences; Blood and lymphatic vessels; candidiasis; Cardiology. Vascular system; CD4-positive T-lymphocytes; Cell Line, Transformed; Child; Child, Preschool; children; chronic mucocutaneous candidiasis; dermatitis; digestive system diseases; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA - metabolism; Female; forkhead box protein 3; Forkhead Transcription Factors - genetics; Fundamental and applied biological sciences. Psychology; Fundamental immunology; fungi; Genes, Dominant; Genetic Diseases, X-Linked - diagnosis; Genetic Diseases, X-Linked - genetics; Genetic Diseases, X-Linked - immunology; Humans; immune dysregulation–polyendocrinopathy–enteropathy–X-linked; Immunopathology; Immunophenotyping; Interferon-alpha - immunology; interferon-gamma; Interferon-gamma - pharmacology; Interleukin-17 - immunology; Interleukin-22; interleukin-6; Interleukins - immunology; Intestinal Diseases - diagnosis; Intestinal Diseases - genetics; Intestinal Diseases - immunology; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Male; Medical sciences; Mutation; mycobacterial diseases; Mycobacterium; neoplasms; patients; Phenotype; phosphorylation; Phosphorylation - drug effects; Polyendocrinopathies, Autoimmune - diagnosis; Polyendocrinopathies, Autoimmune - genetics; Polyendocrinopathies, Autoimmune - immunology; regulatory T cell; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal transducer and activator of transcription 1; signal transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Syndrome; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; transcription factors; Transcriptional Activation; STAT1; Treg; Signal transducer and activator of transcription 1; IVIG; CFSE; regulatory T cell; chronic mucocutaneous candidiasis; FOXP3; forkhead box protein 3; APC; RSV; CMC; GAS; IPEX; immune dysregulation–polyendocrinopathy–enteropathy–X-linked; WT; aneurysms; Gamma activating sequence; Intravenous immunoglobulin; Wild-type; Respiratory syncytial virus; Carboxyfluorescein succinimidyl ester; Regulatory T; Antigen-presenting cell; Immunopathology; Candidiasis; Mycosis; Aneurysm; Cardiovascular disease; Wild type; Protein; Infection; Vascular disease; Transcription factor STAT1; Chronic; Immunology; T-Lymphocyte; Genetics; Mucocutaneous; immune dysregulation―polyendocrinopathy―enteropathy―X-linked; Mutation; Regulatory cell; Transcription factor FOXP3
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2012.11.054

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. We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. 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. 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. Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.