STAT1 is a key component of Interferon (IFN)-γ and IFN-a signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-a driven ISRE response, but not IFN-a driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-a induced immune function.

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Journal of Clinical Immunology
Department of Internal Medicine

Sampaio, E.P, Bax, H.I, Hsu, A.P, Kristosturyan, E, Pechacek, J, Chandrasekaran, P, … Holland, S.M. (2012). A novel STAT1 mutation associated with disseminated mycobacterial disease. Journal of Clinical Immunology, 32(4), 681–689. doi:10.1007/s10875-012-9659-2