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

Subjects affected by STAT1 deficiency have lethal bacterial and viral infections. Here, we report a patient who developed disseminated mycobacteriosis early in life and had severalviral infections. Molecular analysis of STAT1 showed a novel homozygous mutation affecting a splice site, leading to exon 3skipping and to synthesis of a lower molecular weight STAT1 protein. This mutation leads to marked reduction of STAT1phosphorylation; the electromobility shift assay showed a complete defect of DNAbinding activity, which accounts for thecomplete 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-gamma and impaired basal cytolytic activity, suggesting that the STAT1-dependentpathway 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 pathogensand viruses.