Erschienen in:
01.08.2012
A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease
verfasst von:
Elizabeth P. Sampaio, Hannelore I. Bax, Amy P. Hsu, Ervand Kristosturyan, Joseph Pechacek, Prabha Chandrasekaran, Michelle L. Paulson, Dalton L. Dias, Christine Spalding, Gulbu Uzel, Li Ding, Elizabeth McFarland, Steven M. Holland
Erschienen in:
Journal of Clinical Immunology
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Ausgabe 4/2012
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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.