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.

中文翻译：

---

Lowe 综合征患者细胞显示出 mTOR 和 RhoGTPase 依赖性表型，可通过雷帕霉素和他汀类药物缓解。

Lowe 综合征 (LS) 是一种 X 连锁发育疾病，其特征是认知缺陷、双侧先天性白内障和肾功能障碍。不幸的是，这种疾病通常由于肾功能衰竭导致受影响儿童过早死亡。尽管这种情况最早是在 1950 年代早期描述的，但受影响的基因 ( OCRL1) 是在 1990 年代初确定的，其病理生理机制尚未完全了解，并且患者没有可用的 LS 特异性治愈方法。在这里，我们报告了在 LS 患者细胞中受到影响的两个重要信号通路。虽然与正常对照相比，RhoGTPase 信号传导异常导致粘附和扩散缺陷，但 PI3K/mTOR 过度激活干扰了初级纤毛组装（在其他肾功能受损的纤毛病中也观察到了这种情况）。重要的是，我们确定了两种 FDA 批准的能够改善这些表型的药物。具体而言，他汀类药物可减轻粘附和扩散异常，而雷帕霉素可促进 LS 患者细胞的纤毛生成。然而，没有一种药物能够缓解这两种表型。基于这些和其他观察，我们推测 Ocrl1 具有双重，支持正确的 RhoGTPase 和 PI3K/mTOR 信号的独立功能。因此，这项研究表明 Ocrl1 缺陷导致信号缺陷，可能需要组合药物治疗来抑制患者的表型和症状。