Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Nat Commun. 2018 May 17;9(1):1960. doi: 10.1038/s41467-018-04193-w.
No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.
目前尚无针对肾病综合征（NS）的有效治疗方法，而 NS 是慢性肾脏病的常见病因。在这里，我们发现 MAGI2、TNS2、DLC1、CDK20、ITSN1 和 ITSN2 这六个不同基因的突变可导致 17 个存在部分治疗敏感性 NS（pTSNS）的家族出现 NS。这些蛋白相互作用，我们阐明了它们在 Rho 样小分子 GTP 酶（RLSG）活性中的作用，并证实了 pTSNS 患者突变体的缺陷。我们发现 CDK20 调节 DLC1。在培养的足细胞中敲低 MAGI2、DLC1 或 CDK20 会降低迁移率。用地塞米松处理可消除 DLC1 或 CDK20 敲低导致的 RhoA 激活，表明 pTSNS 患者和这些基因突变患者的类固醇治疗是通过该 RLSG 模块介导的。此外，我们发现 ITSN1 和 ITSN2 是足细胞中的 Cdc42 鸟嘌呤核苷酸交换因子。我们生成了缺失 Itsn2-L 的小鼠，其可重现轻度 NS 表型。因此，我们定义了一个 RhoA 调节的功能网络，从而揭示了潜在的治疗靶点。
