Figure 1.

(A) Summary of loss-of-function STAT1 mutations. The N-terminal domain, coiled-coil domain, DNA-binding domain, linker domain, SH2 domain, tail segment domain (TS), and transactivation domain (TA) are shown, together with Y701, the site of tyrosine phosphorylation. The dominant-negative mutants (blue) are indicated below the protein and the recessive forms of hypomorphic (green) and loss-of-function mutations (yellow) are shown above the protein. Y701C is shown in red. (B) The heterozygous Y701C mutation was detected in the patient (II.2) and his mother (I.2). Closed symbols indicate an affected individual and open symbols indicate a healthy family member. (C) CD14-positive monocytes were incubated in the presence of lipopolysaccharide (LPS) (100 ng/mL) and various concentrations of IFN-γ for 48 h and TNF production was then analyzed. CD14-positive monocytes from the patients (P1 and P2) produced abnormally small amounts of TNF. Two independent experiments were performed. (D) Flow cytometry analysis of STAT1 phosphorylation upon IFN-γ stimulation, on peripheral monocytes (CD14⁺ gate). STAT1 phosphorylation levels were lower in the patients’ cells than in control cells. The black line indicates an absence of stimulation and the red line, stimulation with 10⁴ IU/mL IFN-γ. Three independent experiments were performed.