Department of Biological Sciences, Purdue University, Hansen Life Sciences Building, Room 321, 201 S. University street, West Lafayette, IN 47907, USA.
Division of Nephrology, Indiana University School of Medicine, 340 W 10th St #6200, Indianapolis, IN 46202, USA.
Hum Mol Genet. 2020 Jun 27;29(10):1700-1715. doi: 10.1093/hmg/ddaa086.
Lowe syndrome (LS) is an X-linked developmental disease characterized by cognitive deficiencies, bilateral congenital cataracts and renal dysfunction. Unfortunately, this disease leads to the early death of affected children often due to kidney failure. Although this condition was first described in the early 1950s and the affected gene (OCRL1) was identified in the early 1990s, its pathophysiological mechanism is not fully understood and there is no LS-specific cure available to patients. Here we report two important signaling pathways affected in LS patient cells. While RhoGTPase signaling abnormalities led to adhesion and spreading defects as compared to normal controls, PI3K/mTOR hyperactivation interfered with primary cilia assembly (scenario also observed in other ciliopathies with compromised kidney function). Importantly, we identified two FDA-approved drugs able to ameliorate these phenotypes. Specifically, statins mitigated adhesion and spreading abnormalities while rapamycin facilitated ciliogenesis in LS patient cells. However, no single drug was able to alleviate both phenotypes. Based on these and other observations, we speculate that Ocrl1 has dual, independent functions supporting proper RhoGTPase and PI3K/mTOR signaling. Therefore, this study suggest that Ocrl1-deficiency leads to signaling defects likely to require combinatorial drug treatment to suppress patient phenotypes and symptoms.
Lowe 综合征（LS）是一种 X 连锁发育性疾病，其特征为认知缺陷、双侧先天性白内障和肾功能障碍。不幸的是，这种疾病会导致受影响的儿童早亡，通常是由于肾衰竭。尽管这种情况在 20 世纪 50 年代初首次被描述，并且受影响的基因（OCRL1）在 90 年代初被确定，但它的病理生理机制尚未完全了解，并且患者没有 LS 特异性治疗方法。在这里，我们报告了 LS 患者细胞中受影响的两个重要信号通路。虽然与正常对照相比，RhoGTPase 信号异常导致黏附和铺展缺陷，但 PI3K/mTOR 的过度激活干扰了初级纤毛的组装（在其他伴有肾功能障碍的纤毛病中也观察到这种情况）。重要的是，我们确定了两种已获 FDA 批准的药物能够改善这些表型。具体来说，他汀类药物减轻了 LS 患者细胞的黏附和铺展异常，而雷帕霉素促进了纤毛生成。然而，没有一种药物能够同时缓解这两种表型。基于这些和其他观察结果，我们推测 Ocrl1 具有双重独立功能，支持适当的 RhoGTPase 和 PI3K/mTOR 信号。因此，本研究表明 Ocrl1 缺失导致信号缺陷，可能需要联合药物治疗来抑制患者表型和症状。
