AUTHOR=Lv Kunlun , Gong Zhuoqing , Fu Yiting , Zhao Sisi , Song Yinggai , Wang Huijun , Lin Zhimiao 

TITLE=A novel loss-of-function variant in STAT1 causes Mendelian susceptibility to mycobacterial disease

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1595389

DOI=10.3389/fcimb.2025.1595389

ISSN=2235-2988

ABSTRACT=IntroductionMendelian Susceptibility to mycobacterial disease (MSMD) is a rare inherited immunodeficiency disorder characterized by increased susceptibility to atypical mycobacterial infections induced by defective IFN-γ pathway.MethodsWe report three patients from a family presenting with multiple osteolytic lesions and cutaneous granulomas due to Mycobacterium marinum infections. Functional studies, including Western blotting and immunofluorescence, assessed phosphorylation and nuclear translocation of the mutant STAT1-Ile707Thr in eukaryotic overexpression systems. A luciferase reporter assay evaluated its transcriptional activity. Additionally, structural analysis using AlphaFold3 predicted the variant’s functional impact.ResultsA novel STAT1 variant (c.2120T>C, p.Ile707Thr) was identified. The STAT1-Ile707Thr mutant exhibited reduced phosphorylation and impaired nuclear translocation compared to wild-type STAT1. The luciferase assay confirmed decreased transcriptional activity. AlphaFold3-based cluster analysis supported a loss-of-function effect of the mutant.DiscussionThis study expands the spectrum of STAT1 variants and microbial pathogens associated with MSMD.