A novel STAT1 loss-of-function mutation associated with Mendelian susceptibility to mycobacterial disease.

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital immune deficiency characterized by susceptibility to weakly virulent mycobacteria. Loss-of-function (LOF) mutation of signal transducer and activator of transcription 1 ( is one of the common genetic causes of MSMD. In this study, we identified a patient who presented with multiple lymph node enlargements and multiple osteolytic disruptions. infection was confirmed by metagenomic next-generation sequencing. Whole-exome sequencing identified a novel paternal heterozygous mutation in exon 22 of (NM_007315.4, c.1892T>C, p.Val631Ala). This variant was confirmed pathogenic by multiple software predictions. Based on functional assays, STAT1 expression in STAT1 cells was not different from STAT1 cells. But STAT1 mutation caused much lower activation of STAT1 when stimulated by interferon-γ (IFN-γ). Fluorescence localization analysis revealed that both STAT1 and STAT1 proteins were located in the cytoplasm, and only a few STAT1 proteins were translocated to the nucleus in response to IFN-γ. These results suggest that STAT1 leads to LOF in IFN-γ-mediated mycobacterial immunity, resulting in MSMD. Treatment with antibiotics has achieved ideal disease control for this patient, and no adverse events occurred during follow-up. The LOF deficiency is a genetic cause of MSMD, which should be considered in patients with mycobacterial disease, especially those with bone involvement.