Kazenwadel Jan, Betterman Kelly L, Chong Chan-Eng, Stokes Philippa H, Lee Young K, Secker Genevieve A, Agalarov Yan, Demir Cansaran Saygili, Lawrence David M, Sutton Drew L, Tabruyn Sebastien P, Miura Naoyuki, Salminen Marjo, Petrova Tatiana V, Matthews Jacqueline M, Hahn Christopher N, Scott Hamish S, Harvey Natasha L
J Clin Invest. 2015 Aug 3;125(8):2979-94. doi: 10.1172/JCI78888. Epub 2015 Jul 27.
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema.
锌指转录因子GATA2的杂合种系突变最近被证明是一系列临床表型的基础，包括恩伯格综合征，这是一种以淋巴水肿和易患骨髓增生异常综合征/急性髓系白血病（MDS/AML）为特征的疾病。尽管GATA2在造血过程中的作用已明确，但它在淋巴管系统中的功能以及GATA2突变导致淋巴水肿的机制尚未得到阐明。在此，我们为一部分携带种系GATA2突变的患者易患淋巴水肿提供了分子解释。具体而言，我们证明与恩伯格综合征相关的GATA2错义突变导致GATA2功能完全丧失，即调节对淋巴管瓣膜发育至关重要的基因转录的能力丧失。我们在关键淋巴转录调节因子PROX1上游鉴定了一个假定的增强子元件，该元件可与GATA2、转录因子FOXC2和NFATC1结合。恩伯格综合征的GATA2错义突变体与该元件结合的能力大幅降低。小鼠中条件性Gata2缺失表明，GATA2对于淋巴静脉和淋巴管瓣膜的发育及维持均必不可少。总之，我们的数据揭示了GATA2在淋巴管系统中的重要作用，并解释了为什么特定的人类GATA2突变会导致淋巴水肿。
