Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Kidney Development, Disease and Regeneration Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Sci Adv. 2021 Jan 1;7(1). doi: 10.1126/sciadv.abe1386. Print 2021 Jan.
Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) , but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT but not by constructs bearing patient variants. PMR in knockdown podocytes was also rescued by constitutively active or the formin Modeling a patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.
肾病综合征（NS）是慢性肾脏病的主要病因之一。我们通过外显子组测序在两个早发性 NS 家系中发现了隐性变异。野生型（WT）的过表达，但不是带有患者变异的 cDNA 构建体，增加了活性 CDC42 并促进了丝状伪足和足突形成。CDC42 或其效应物formin 蛋白的药理学抑制减少了 NOS1AP 诱导的丝状伪足形成。NOS1AP 敲低降低了足细胞迁移率（PMR），而 WT 的过表达可以挽救 PMR，但患者变异的构建体则不能。NOS1AP 敲低足细胞中的 PMR也可以通过组成型激活 CDC42 或 formin 蛋白来挽救。在敲入人类肾类器官中模拟一个患者变异体显示出具有增加的细胞凋亡的畸形肾小球。NOS1AP 敲除小鼠重现了人类表型，表现为蛋白尿、足突消失和肾小球硬化。这些发现表明隐性 NOS1AP 变异体损害了 CDC42/DIAPH 依赖的肌动蛋白重塑，导致异常的类器官肾小球发生，并导致人类和小鼠的肾小球病。
