Severe impairment of IFN-γ and IFN-α responses in cells of a patient with a novel STAT1 splicing mutation

Subjects affected by Signal Transducer and Activator of Transcription 1 (STAT1) deficiency have lethal bacterial and viral infections. Complete STAT1 deficiency is inherited as an autosomal recessive disease; partial STAT1 deficiency is inherited as an autosomal recessive or autosomal dominant trait. Here, we report a patient who developed disseminated mycobacteriosis early in life and had several viral infections, including herpetic skin infection and interstitial pneumonia by cytomegalovirus with severe respiratory distress. Molecular analysis of STAT1 showed a novel homozygous mutation affecting a splice site, leading to exon 3 skipping and to synthesis of a lower molecular weight STAT1 protein. This mutation leads to marked reduction of STAT1 phosphorylation; the electromobility shift assay showed a complete defect of DNA-binding activity, which accounts for the complete impairment of peripheral blood mononuclear cell functional response to both IFN-gamma and IFN-alpha. Moreover, analysis of natural killer cells showed a defective STAT1 phosphorylation in response to IFN-alpha and impaired basal cytolytic activity, suggesting that the STAT1-dependent pathway might be important for natural killer cell function. These results suggested that exon 3 skipping of STAT1 leads to abnormal signaling in response to IFN-gamma and IFN-alpha, which is associated with susceptibility to intracellular pathogens and viruses. (Blood. 2011; 118(7): 1806-1817)