Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

Shazia Ashraf, Hiroki Kudo, Jia Rao, Atsuo Kikuchi, Eugen Widmeier, Jennifer A. Lawson, Weizhen Tan, Tobias F. Hermle, Jillian K. Warejko, Shirlee Shril

55 more authors

Merlin Airik, Tilman Jobst‐Schwan, Svjetlana Lovric, Daniela Anne Braun, Heon Yung Gee, David Schapiro, Amar J. Majmundar, Carolin E. Sadowski, Werner L. Pabst, Ankana Daga, Amelie T. van der Ven, Johanna Magdalena Schmidt, Boon Chuan Low, Anjali Bansal Gupta, Brajendra K. Tripathi, Jenny Wong, Kirk Nicholas Campbell, Kay Metcalfe, Denny Schanze, Tetsuya Niihori, Hiroshi Kaito, Kandai Nozu, Hiroyasu Tsukaguchi, Ryojiro Tanaka, Kiyoshi Hamahira, Yasuko Kobayashi, Takumi Takizawa, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Naonori Kumagai, Kazumoto Iijima, Henry Fehrenbach, Jameela Abdulaziz Kari, Sherif Mohamed El Desoky, Sawsan M. Jalalah, Radovan Bogdanović, Nataša Stajić, H. Zappel, Assel Rakhmetova, Sharon-Rose Wassmer, Therese Jungraithmayr, Juergen Strehlau, Aravind Selvin Kumar Ramanathan, Arvind Bagga, Neveen A. Soliman, Shrikant Mane, Lewis Kaufman, Douglas R. Lowy, Mohamad Aman Jairajpuri, Richard P. Lifton, York Pei, Martin Zenker, Shigeo Kure, Friedhelm Hildebrandt

Nature Communications, 2018

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DOI 10.1038/s41467-018-04193-w
Data confidence 85 high
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Abstract

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.