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Made available in DSpace on 2018-11-26T17:44:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-12-15 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Background. Mutations in genes affecting interferon-gamma (IFN-gamma) immunity have contributed to understand the role of IFN-gamma in protection against intracellular pathogens. However, inborn errors in STAT4, which controls interleukin-12 (IL-12) responses, have not yet been reported. Our objective was to determine the genetic defect in a family with a history of paracoccidioidomycosis. Methods. Genetic analysis was performed by whole-exome sequencing and Sanger sequencing. STAT4 phosphorylation (pSTAT4) and translocation to the nucleus, IFN-gamma release by patient lymphocytes, and microbicidal activity of patient monocytes/macrophages were assessed. The effect on STAT4 function was evaluated by site-directed mutagenesis using a lymphoblastoid B cell line (B-LCL) and U3A cells. Results. A heterozygous missense mutation, c.1952 A > T (p.E651V) in STAT4 was identified in the index patient and her father. Patient's and father's lymphocytes showed reduced pSTAT4, nuclear translocation, and impaired IFN-gamma production. Mutant B-LCL and U3A cells also displayed reduced pSTAT4. Patient's and father's peripheral blood mononuclear cells and macrophages demonstrated impaired fungicidal activity compared with those from healthy controls that improved in the presence of recombinant human IFN-gamma, but not rhIL-12. Conclusion. Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-gamma immunity associated with susceptibility to paracoccidioidomycosis. Univ Sao Paulo, Dept Immunol, Sao Paulo, Brazil Univ Lubeck, Dept Rheumatol & Clin Immunol, Lubeck, Germany Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA Seattle Childrens Res Inst, Seattle, WA USA Rockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA Sao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, Brazil Butantan Inst, Lab Biochem & Biophys, Sao Paulo, Brazil Univ Sao Paulo, Human Genome & Stem Cell Res Ctr, Sao Paulo, Brazil Paris Descartes Univ, Imagine Inst, Paris, France Necker Hosp Sick Children, Lab Human Genet Infect Dis, Paris, France Necker Hosp Sick Children, Ctr Study Primary Immunodeficiencies, Paris, France Necker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris, France Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA Univ Sao Paulo, Inst Trop Med, Sao Paulo, Brazil Sao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, Brazil FAPESP: 2011/2507-1 FAPESP: 2/51745-3 FAPESP: 13/50303-0