2011年首次发现种系人类杂合STAT1功能获得(GOF)变异是慢性粘膜皮肤念珠菌病(CMC)的常见原因。从那以后,已经鉴定了许多STAT1GOF变体。多种临床表型,包括真菌,病毒,和细菌感染,内分泌失调,自身免疫,恶性肿瘤,和动脉瘤,最近发现了STAT1GOF变体,这导致了与STAT1GOF相关的临床范围的扩大。在这些广泛的并发症中,已经确定侵入性感染,动脉瘤,恶性肿瘤是STAT1GOF的不良预后因素。JAK抑制剂作为治疗选择的有效性已经确立,尽管需要进一步研究其长期效用和副作用。与治疗方案的进步相反,STAT1GOF的确切分子机制仍未确定。该机制的两个主要假设涉及受损的STAT1去磷酸化和增加的STAT1蛋白水平。这两者仍然是有争议的。对分子机制的精确理解不仅对于推进诊断,而且对于开发治疗干预措施至关重要。这里,我们对STAT1GOF进行了全面综述,目的是在床边观察和实验室研究之间建立更紧密的联系.
Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF. The effectiveness of JAK inhibitors as a therapeutic option has been established, although further investigation of their long-term utility and side effects is needed. In contrast to the advancements in treatment options, the precise molecular mechanism underlying STAT1 GOF remains undetermined. Two primary hypotheses for this mechanism involve impaired STAT1 dephosphorylation and increased STAT1 protein levels, both of which are still controversial. A precise understanding of the molecular mechanism is essential for not only advancing diagnostics but also developing therapeutic interventions. Here, we provide a comprehensive review of STAT1 GOF with the aim of establishing a stronger connection between bedside observations and laboratory research.