Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Sci Immunol. 2018 Jun 15;3(24). doi: 10.1126/sciimmunol.aat4941.
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of mutations. We identified two distinct homozygous nonsense mutations in , which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
信号转导子和转录激活子 3（STAT3）是免疫稳态的中央调节因子。STAT3 水平受到严格控制，STAT3 功能障碍会导致多种疾病，包括单基因常染色体显性高免疫球蛋白 E（IgE）综合征（AD-HIES）。我们研究了四个有血缘关系的家系的患者，他们患有类似于 AD-HIES 表型的常染色体隐性疾病，表现为免疫缺陷、反复感染、骨骼异常和 IgE 升高。患者表现出 STAT3 表达降低和辅助性 T 细胞 17 细胞数量减少，而无 突变。我们在 中鉴定出两个不同的纯合无义突变，该基因编码锌指转录因子。野生型 ZNF341 与 启动子结合并激活其转录，而突变变体显示转录激活受损，部分原因是核易位失败。总之，四个常染色体隐性家系中的无义突变导致了类似 STAT3 的表型。因此，ZNF341 是免疫稳态的一个以前未被识别的调节因子。
