RATIONALE Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches. OBJECTIVE Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders. METHODS AND RESULTS Whole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice Conclusions: Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.

中文翻译：

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努南综合征基因 Lztr1 通过调节囊泡运输来控制心血管功能。


基本原理 努南综合征 (NS) 是最常见的遗传性疾病之一。出血问题是与 NS 相关的最常见但定义不明确的并发症之一。对于 NS 患者出血并发症的治疗缺乏共识，表明迫切需要新的治疗方法。目的 最近描述了携带 LZTR1（亮氨酸拉链样转录调节因子 1）突变的 NS 患者的出血性疾病，LZTR1 是 CUL3 (CULLIN3) 泛素连接酶复合物的接头。在这里，我们评估了 LZTR1 介导的出血性疾病的病理学。方法和结果 Lztr1 的全身和血管特异性敲除会导致围产期因心血管功能障碍而死亡。成年小鼠血管中 Lztr1 缺失会导致异常血管渗漏。我们发现 Lztr1 耗尽的内皮细胞中有缺陷的粘附和紧密连接是由囊泡运输失调引起的。 LZTR1 通过控制 ESCRT-III（转运 III 所需的内体分选复合物）成分 CHMP1B（带电多囊泡蛋白 1B）的泛素化来影响回收内体的融合和裂变动力学，而 NS 相关的 LZTR1 突变会减弱 CHMP1B 泛素化。 LZTR1 介导的 CHMP1B 泛素化失调会触发内体积聚并随后激活 VEGFR2（血管内皮生长因子受体 2），并降低 Lztr1 单倍体不足小鼠中可溶性 VEGFR2 的血液水平。西地尼布抑制 VEGFR2 活性可挽救 Lztr1 敲除小鼠中观察到的血管异常。 结论：Lztr1 缺失表型与 NS 患者中观察到的出血素质重叠。 对 LZTR1 突变的 NS 患者血液中可溶性 VEGFR2 进行 ELISA 筛查，可以预测 NS 表型的严重程度和对抗 VEGF 治疗的潜在反应者。 VEGFR 抑制剂可能有益于治疗 NS 患者的出血性疾病。