The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking.
The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking.
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DOI：
10.1161/circresaha.119.315730
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发表时间：
2020-05-08
影响因子：
20.1
通讯作者：
Sablina AA
中科院分区：
文献类型：
--
作者：
Sewduth RN;Pandolfi S;Steklov M;Sheryazdanova A;Zhao P;Criem N;Baietti MF;Lechat B;Quarck R;Impens F;Sablina AA
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清的并发症之一。NS患者出血并发症的处理缺乏共识，这表明迫切需要新的治疗方法。最近有报道称，NS患者携带LZTR1突变，LZTR1是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生物学。Lztr1的全身和血管特异性敲除可导致围产期心血管功能障碍致死。成年小鼠血管中Lztr1缺失导致血管异常渗漏。我们发现lztr1缺失的内皮细胞的粘附缺陷和紧密连接是由囊泡运输失调引起的。LZTR1通过控制ESCRT-III组分CHMP1B的泛素化来影响再循环核内体的融合和裂变动力学，而ns相关的LZTR1突变会减少CHMP1B的泛素化。Lztr1介导的CHMP1B泛素化失调触发内体积聚和随后的VEGFR2激活，并降低Lztr1单倍体不足小鼠血液中可溶性VEGFR2水平。cediranib对VEGFR2活性的抑制可挽救Lztr1基因敲除小鼠中观察到的血管异常。Lztr1缺失的表型与NS患者中观察到的出血特征重叠。ELISA筛选lztr1突变的NS患者血液中可溶性VEGFR2可以预测NS表型的严重程度和抗vegf治疗的潜在反应。VEGFR抑制剂可能有利于NS患者出血性疾病的治疗
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 NS patients indicates an urgent need for new therapeutic approaches. Bleeding disorders have recently been described in NS patients harboring mutations of LZTR1, an adaptor for CULLIN3 ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders. 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 component CHMP1B, whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 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 Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in NS patients. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated NS patients 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 NS patients