Signal transducer and activator of transcription 1 (STAT1) regulates multiple biological processes downstream of a variety of cytokine receptors in many cell types. Heterozygous gain-of-function (GOF) mutations in STAT1 have been associated with a diverse phenotype encompassing chronic mucocutaneous candidiasis (CMCC) and declining immunity. There is no clear correlation between STAT1 domain-specific mutations and phenotype, and it remains unclear why GOF mutations in STAT1 result in such a wide spectrum of clinical presentations. To begin exploring this dilemma, we have studied the patterns of gene expression mediated by two different GOF mutations. Analysis of IFN-γ response elements using RNA microarrays in cells transfected with the rare H629Y mutant or the common R274G mutant showed distinct patterns of gene expression. We show here that the impact of GOF mutations in STAT1 is variant-specific. This difference in gene expression may explain the diversity in clinical manifestations experienced by these patients.

信号转导和转录激活因子1（STAT1）调节许多细胞类型中各种细胞因子受体下游的多个生物过程。STAT1中的杂合功能获得（GOF）突变已与多种表型相关，包括慢性粘膜皮肤念珠菌病（CMCC）和免疫力下降。STAT1结构域特异性突变与表型之间没有明确的相关性，并且尚不清楚为什么STAT1中的GOF突变会导致如此广泛的临床表现。为了开始探索这个难题，我们研究了由两个不同的GOF突变介导的基因表达模式。使用罕见的H629Y突变体或常见的R274G突变体转染的细胞中使用RNA微阵列分析IFN-γ响应元件显示出不同的基因表达模式。我们在这里显示STAT1中GOF突变的影响是变体特异性的。基因表达的这种差异可能解释了这些患者经历的临床表现的多样性。