title: A novel STAT1 mutation associated with disseminated mycobacterial disease.
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.
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.|Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Manguinhos, Rio de Janeiro, RJ, Brazil.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Sampaio
authors.affiliation: 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.
authors.forename: Hannelore I
authors.initials: HI
authors.lastname: Bax
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Ervand
authors.initials: E
authors.lastname: Kristosturyan
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pechacek
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Prabha
authors.initials: P
authors.lastname: Chandrasekaran
authors.affiliation: Clinical Research Directorate/CMRP, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, 21702.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Paulson
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Dalton L
authors.initials: DL
authors.lastname: Dias
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Spalding
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Section of Infectious Diseases, Department of Pediatrics, Children's Hospital Colorado, UC, Denver, CO.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McFarland
authors.affiliation: Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D001402:B-Lymphocytes; D002460:Cell Line; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D009165:Mycobacterium Infections, Nontuberculous / Q000235:genetics* / Q000382:microbiology; D015269:Mycobacterium avium Complex / Q000472:pathogenicity*; D010766:Phosphorylation; D055503:Protein Multimerization; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma