title: Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection.
abstract: IFN-gamma is critical in the immune response to mycobacterial infections, and deficits in IFN-gamma production and response have been associated with disseminated nontuberculous mycobacterial infections. Mutations in the IFN-gamma receptor ligand-binding chain (IFNgammaR1) have been shown to confer susceptibility to severe infection with nontuberculous mycobacteria. However, mutations in the IFN-gamma receptor signal-transducing chain (IFNgammaR2) have not been described. We describe a child with disseminated Mycobacterium fortuitum and M. avium complex infections and absent IFN-gamma signaling due to a mutation in the extracellular domain of IFNgammaR2. In vitro cytokine production by patient PBMCs showed 75% less PHA-induced IFN-gamma production than in normal cells, while patient PHA-induced TNF-alpha production was normal. The normal augmentation of TNF-alpha production when IFN-gamma was added to endotoxin was absent from patient cells. Expression of IFNgammaR1 was normal, but there was no phosphorylation of Stat1 in response to IFN-gamma stimulation. DNA sequence analysis of the gene for IFNgammaR2 showed a homozygous dinucleotide deletion at nucleotides 278 and 279, resulting in a premature stop codon in the protein extracellular domain. This novel gene defect associated with disseminated nontuberculous mycobacterial infection emphasizes the critical role that IFN-gamma plays in host defense against mycobacteria.
authors.affiliation: Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1886, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Dorman
authors.forename: S M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D009154:Mutation; D009164:Mycobacterium Infections / Q000276:immunology*; D011247:Pregnancy; D017471:Receptors, Interferon / Q000235:genetics*; D015398:Signal Transduction; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor