Abstract：
Primary lymphedema (PL), characterized by tissue swelling, fat accumulation and fibrosis, results from defective lymphatic vessels or valves caused by mutations in genes involved in development, maturation and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodelling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR-Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2-TIE1 pathway in lymphatic function.
摘要：
原发性淋巴水肿（PL），以组织肿胀为特征，脂肪积累和纤维化，由参与发育的基因突变引起的淋巴管或瓣膜缺陷的结果，淋巴管系统的成熟和功能。已经在约30%的PL病例中鉴定了各种基因中的致病变体。通过筛选755名PL患者的队列，我们确定了两个TIE1（具有免疫球蛋白和表皮生长因子样结构域的酪氨酸激酶1）错义变体和一个截短变体，通过生物信息学算法预测所有这些都是致病的。TIE1受体，与TIE2复合，结合血管生成素以调节血液和淋巴管的形成和重塑。提前终止密码子突变体编码具有降低的mRNA稳定性的无活性的截短的细胞外TIE1片段,并且氨基酸取代导致降低的TIE1信号传导活性。通过CRISPR-Cas9在小鼠Tie1中复制两个错义变体，我们表明两者都会引起水肿，并且在纯合小鼠中致死。因此，我们的结果表明,TIE1功能缺失变异体可导致患者淋巴功能障碍.结合我们先前的证明，ANGPT2功能丧失突变也可以导致PL，我们的研究结果强调了ANGPT2-TIE1通路在淋巴功能中的重要作用.
