Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.
Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.
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DOI：
10.1172/jci.insight.152102
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发表时间：
2022-01-25
期刊：
影响因子：
8
通讯作者：
Gbadegesin, Rasheed
中科院分区：
文献类型：
--
作者：
Lane, Brandon M.;Chryst-Stangl, Megan;Wu, Guanghong;Shalaby, Mohamed;El Desoky, Sherif;Middleton, Claire C.;Huggins, Kinsie;Sood, Amika;Ochoa, Alejandro;Malone, Andrew F.;Vancini, Ricardo;Miller, Sara E.;Hall, Gentzon;Kim, So Young;Howell, David N.;Kari, Jameela A.;Gbadegesin, Rasheed
我们对家族性类固醇敏感肾病综合征（SSNS）患者进行了新一代测序，并在一个有3名患者的近亲家庭中发现了编码clavesin-1 （CLVS1）基因的纯合分离变异（p.H310Y）。敲低斑马鱼clavesin基因（clvs2）会产生水肿表型，这是由于足细胞结构的破坏和肾小球滤过屏障完整性的丧失，而WT CLVS1可以挽救这些表型，而p.H310Y变体则不能。通过CRISPR/ cas9介导的CLVS1敲除或纯合子H310Y敲除对培养的人足细胞进行分析，发现网格蛋白介导的内噬缺陷和细胞凋亡易感性增加，可以通过皮质类固醇治疗来挽救，模拟SSNS患者的类固醇反应性。p.H310Y变异还破坏了clavesin-1与α-生育酚转移蛋白的结合，导致clvs1缺陷足细胞中活性氧（ROS）积累增加。用药理学ROS抑制剂治疗clvs1敲除或纯合子h310y敲除足细胞可将活力恢复到控制水平。综上所述，这些数据确定了CLVS1是SSNS的候选基因，为皮质类固醇对足细胞细胞动力学的治疗作用提供了见解，并为内吞作用和氧化应激调节对足细胞功能的重要性提供了越来越多的证据。
We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased reactive oxygen species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.
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影响因子：
3.6
作者：
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