Abstract
STAT1 is a key component of Interferon (IFN)-γ and IFN-α 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-α driven ISRE response, but not IFN-α 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-α induced immune function.
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Acknowledgements
The research was supported by the Division of Intramural Research of National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
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The authors declare that they have no conflict of interest.
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Elizabeth P. Sampaio and Hannelore I. Bax contributed equally to this work
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Sampaio, E.P., Bax, H.I., Hsu, A.P. et al. A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease. J Clin Immunol 32, 681–689 (2012). https://doi.org/10.1007/s10875-012-9659-2
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DOI: https://doi.org/10.1007/s10875-012-9659-2