Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

中文翻译：

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激活STAT3突变的不同分子反应模式与淋巴增殖和自身免疫的外显率有关。

生殖细胞STAT3功能获得（GOF）突变已与多自体免疫和淋巴增殖相关，且具有可变的表达能力和不完全的外显率。在这里，我们研究了17种不同的STAT3 GOF突变对经典STAT3信号通路的影响，并将分子结果与临床表现相关联。突变分为三类。第1组突变体显示STAT3磷酸化动力学改变和强大的基础转录活性。它们与淋巴增殖和自身免疫的最高外显率相关。第2组突变体表现出强烈诱导的转录报告基因活性，并且在临床上渗透性较低。第3组突变体大多位于DNA结合域中，尽管转录报告反应较差，但显示出最强的DNA结合亲和力。因此，STAT3突变的GOF效应由分子水平上的异质反应模式决定。应答模式与临床表现的相关性表明，突变决定的效应对疾病表现的重要贡献。