Severe Impairment of IFN-α and IFN-γ Responses in Cells of a Patient with a Rare STAT1 Tail Segment Domain Mutation

Abstract

Signal transducer and activator of transcription 1 (STAT1) mutations are associated with diverse pathologies. Loss-of-function (LOF) heterozygous mutations impair interferon (IFN) signaling, predisposing to Mendelian susceptibility to mycobacterial diseases (MSMDs). This study characterizes a novel STAT1 LOF mutation in a patient with multisystem manifestations. A patient presenting with mycobacterial infection, skeletal abnormalities, and systemic inflammation underwent whole-exome sequencing. The identified STAT1 variant was analyzed via computational tools (PolyPhen-2/SIFT). Molecular biological validation included IFN-α/γ-induced STAT1 phosphorylation assays and fluorescence microscopy for subcellular localization. Clinical features included mycobacterial osteomyelitis, severe rash, dwarfism, hepatosplenomegaly, and elevated inflammatory markers (C-reactive protein/erythrocyte sedimentation rate). A heterozygous STAT1 mutation (NM_007315.4:c.2120T>C; p.Ile707Thr) was identified and predicted as pathogenic. Mutant cells showed reduced STAT1 phosphorylation (64% versus wild-type, P < 0.05) and impaired nuclear translocation post-IFN-α/γ stimulation. Antibiotic therapy achieved clinical resolution without complications. These findings indicated that the STAT1 I707T mutation disrupts IFN-α/γ immunity, expanding the MSMD genotypic spectrum. Genetic screening for STAT1 defects is critical in patients with mycobacterial infections involving skin. Molecular biological studies corroborate mutation pathogenicity, guiding therapeutic decisions.