Severe impairment of IFN-I and IFN-II responses in cells of a patient with a rare STAT1 TSD Mutation

Mutations in Signal Transducer and Activator of Transcription 1 (STAT1) are linked to various disease phenotypes. Loss-of-function (LOF) mutations in STAT1, particularly in heterozygous forms, contribute to Mendelian susceptibility to mycobacterial diseases (MSMD) due to impaired interferon-II (IFN-II) signalling. Identifying novel mutations expands the spectrum of conditions associated with autosomal dominant (AD) STAT1 deficiency. This case study reports a patient presenting with mycobacterial infection, severe rash, dwarfism, hepatosplenomegaly, and elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The computed tomography (CT) imaging revealed bone damage. Whole-exome sequencing identified a heterozygous STAT1 mutation in exon 23 (NM_007315.4: c.2120T>C; p.Ile707Thr), predicted to be pathogenic by multiple computational tools. Functional assays demonstrated that STAT1 I707T-mutant cells exhibited reduced STAT1 activation in response to IFN-II plasmic, with limited nuclear translocation following IFN-II stimulation. These results indicate that the STAT1 I707T mutation impairs IFN-II-mediated mycobacterial immunity, leading to MSMD. The patient responded well to antibiotic treatment, with no adverse events reported during follow-up. This case emphasises the significance of STAT1 LOF deficiency in MSMD and highlights the need to consider genetic screening in individuals with mycobacterial infections, particularly those affecting the bones. Further studies are warranted to explore the potential systemic effects of this mutation.