Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment.
Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment.
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DOI：
10.1038/s41467-018-04193-w
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发表时间：
2018-05-17
影响因子：
16.6
通讯作者：
Hildebrandt F
中科院分区：
文献类型：
--
作者：
Ashraf S;Kudo H;Rao J;Kikuchi A;Widmeier E;Lawson JA;Tan W;Hermle T;Warejko JK;Shril S;Airik M;Jobst-Schwan T;Lovric S;Braun DA;Gee HY;Schapiro D;Majmundar AJ;Sadowski CE;Pabst WL;Daga A;van der Ven AT;Schmidt JM;Low BC;Gupta AB;Tripathi BK;Wong J;Campbell K;Metcalfe K;Schanze D;Niihori T;Kaito H;Nozu K;Tsukaguchi H;Tanaka R;Hamahira K;Kobayashi Y;Takizawa T;Funayama R;Nakayama K;Aoki Y;Kumagai N;Iijima K;Fehrenbach H;Kari JA;El Desoky S;Jalalah S;Bogdanovic R;Stajić N;Zappel H;Rakhmetova A;Wassmer SR;Jungraithmayr T;Strehlau J;Kumar AS;Bagga A;Soliman NA;Mane SM;Kaufman L;Lowy DR;Jairajpuri MA;Lifton RP;Pei Y;Zenker M;Kure S;Hildebrandt F
肾病综合征（NS）是慢性肾脏疾病的常见病因，目前尚无有效的治疗方法。本研究显示，在17个部分治疗敏感性NS （pTSNS）家族中，6个不同基因（MAGI2、TNS2、DLC1、CDK20、ITSN1、ITSN2）突变可导致NS。这些蛋白相互作用，我们描述了它们在rho样小GTPase （RLSG）活性中的作用，并证明了pTSNS患者突变体的缺陷。我们发现CDK20调控DLC1。在培养足细胞中敲低MAGI2、DLC1或CDK20可降低迁移率。地塞米松治疗通过敲低dcl1或CDK20来消除RhoA激活，这表明pTSNS患者的类固醇治疗和这些基因的突变是由RLSG模块介导的。此外，我们发现ITSN1和ITSN2是Cdc42的足细胞鸟嘌呤核苷酸交换因子。我们产生了Itsn2-L基因敲除小鼠，再现了轻度NS表型。因此，我们定义了RhoA调节的功能网络，从而揭示了潜在的治疗靶点。肾病综合征是第二常见的慢性肾脏疾病，但目前尚无针对性的治疗策略。在这里，作者在17个肾病综合征家族中发现了6个基因的突变，这些基因编码了参与细胞骨架重塑和小gtp酶调节的蛋白质。
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. Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.
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影响因子：
1.7
作者：
Alwadhi, RK;Mathew, JL;Rath, B
通讯作者：
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影响因子：
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Dahlbäck, B
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通讯作者：
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Gee, Heon Yung;Zhang, Fujian;Hildebrandt, Friedhelm
通讯作者：
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