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.

中文翻译：

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人类 STAT1 与慢性皮肤粘膜念珠菌病的功能获得：加强床边观察和实验室研究之间联系的全面综述

人类种系杂合STAT1功能获得 (GOF) 变异体于 2011 年首次被发现是慢性皮肤粘膜念珠菌病 (CMC) 的常见原因。此后，已鉴定出多种STAT1 GOF 变异体。最近揭示了STAT1 GOF 变异的多种临床表型，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，这导致了与STAT1 GOF 相关的临床谱的扩展。在这些广泛的并发症中，已确定侵袭性感染、动脉瘤和恶性肿瘤是STAT1 GOF 的不良预后因素。JAK 抑制剂作为一种治疗选择的有效性已经得到证实，但还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比，STAT1 GOF 的精确分子机制仍未确定。该机制的两个主要假设涉及 STAT1 去磷酸化受损和 STAT1 蛋白水平增加，这两者仍然存在争议。准确理解分子机制不仅对于推进诊断而且对于开发治疗干预措施都至关重要。在这里，我们对STAT1 GOF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。