Lv Kunlun, Gong Zhuoqing, Fu Yiting, Zhao Sisi, Song Yinggai, Wang Huijun, Lin Zhimiao
Dermatology Hospital, Southern Medical University, Guangzhou, China.
Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing, China.
Front Cell Infect Microbiol. 2025 May 26;15:1595389. doi: 10.3389/fcimb.2025.1595389. eCollection 2025.
Mendelian 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.
We 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.
A 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.
This study expands the spectrum of STAT1 variants and microbial pathogens associated with MSMD.
孟德尔遗传性分枝杆菌病易感性（MSMD）是一种罕见的遗传性免疫缺陷疾病，其特征是由于干扰素-γ途径缺陷导致对非典型分枝杆菌感染的易感性增加。
我们报告了来自一个家族的三名患者，他们因海分枝杆菌感染出现多处溶骨性病变和皮肤肉芽肿。在真核过表达系统中，通过蛋白质印迹和免疫荧光等功能研究评估了突变型STAT1-Ile707Thr的磷酸化和核转位。荧光素酶报告基因测定评估了其转录活性。此外，使用AlphaFold3进行的结构分析预测了该变体的功能影响。
鉴定出一种新的STAT1变体（c.2120T>C，p.Ile707Thr）。与野生型STAT1相比，STAT1-Ile707Thr突变体的磷酸化减少且核转位受损。荧光素酶测定证实转录活性降低。基于AlphaFold3的聚类分析支持该突变体的功能丧失效应。
本研究扩展了与MSMD相关的STAT1变体和微生物病原体的范围。
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