A novel STAT1 mutation associated with disseminated mycobacterial disease.

Autor: Sampaio EP; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.; Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Manguinhos, Rio de Janeiro, RJ, Brazil., Bax HI; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.; Department of Internal Medicine and Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, the Netherlands., Hsu AP; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Kristosturyan E; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Pechacek J; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Chandrasekaran P; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Paulson ML; Clinical Research Directorate/CMRP, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, 21702., Dias DL; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Spalding C; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Uzel G; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., Ding L; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA., McFarland E; Section of Infectious Diseases, Department of Pediatrics, Children's Hospital Colorado, UC, Denver, CO., Holland SM; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: Journal of clinical immunology [J Clin Immunol] 2012 Aug; Vol. 32 (4), pp. 681-689. Date of Electronic Publication: 2012 Feb 29.
DOI: 10.1007/s10875-012-9659-2
Abstrakt: 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.
Databáze: MEDLINE
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