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 Hermle, Jillian K. Warejko, Shirlee Shril, Merlin Airik, Tilman Jobst-Schwan, Svjetlana Lovric, Daniela A. Braun, Heon Yung Gee, David Schapiro, Amar J. Majmundar, Carolin E. Sadowski, Werner L. Pabst, Ankana DagaAmelie T. Van Der Ven, Johanna M. Schmidt, Boon Chuan Low, Anjali Bansal Gupta, Brajendra K. Tripathi, Jenny Wong, Kirk 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 A. Kari, Sherif El Desoky, Sawsan Jalalah, Radovan Bogdanovic, Nataša Stajić, Hildegard Zappel, Assel Rakhmetova, Sharon Rose Wassmer, Therese Jungraithmayr, Juergen Strehlau, Aravind Selvin Kumar, Arvind Bagga, Neveen A. Soliman, Shrikant M. Mane, Lewis Kaufman, Douglas R. Lowy, Mohamad A. Jairajpuri, Richard P. Lifton, York Pei, Martin Zenker, Shigeo Kure, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

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.

Original languageEnglish
Article number1960
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Bibliographical note

Funding Information:
We are grateful to study individuals for their contribution. We acknowledge the Yale Center for Mendelian Genomics for whole exome sequencing. This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and by the Howard Hughes Medical Institute to F.H. F.H. is the William E. Harmon Professor of Pediatrics. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). W.T. is supported by the ASN Foundation for Kidney Research. T.H. is supported by the DFG-fellowship (HE 7456/1-1). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). H.Y.G. is supported by the National Research Foundation of Korea, Ministry of Science, ICT, and Future planning (2015R1D1A1A01056685) and faculty seed money from the Yonsei University College of Medicine (2015-32-0047). A.T.v.d.V. is supported by the DFG-fellowship (VE 196/1-1). We thank Yoko Chiba, Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, Yoko Tateda and Kiyotaka Kuroda for their technical assistance. This work was supported by grants (17ek0109151h0003 and 17ek0109278h0001) from Japan Agency for Medical Research and Development (AMED) to S.K. We acknowledge the support of the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core and the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine. N.A.S is supported by the Egyptian Group for Orphan Renal Diseases (EGORD). M.A.J. is supported by Department of Science and Technology, Govt. of India (DST-SERB). M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423).

Funding Information:
This research was supported by grants from the National Institutes of Health to F.H. (DK076683) and by the Howard Hughes Medical Institute to F.H. F.H. is the William E. Harmon Professor of Pediatrics. E.W. is supported by the German National Academy of Sciences Leopoldina (LPDS-2015-07). W.T. is supported by the ASN Foundation for Kidney Research. T.H. is supported by the DFG-fellowship (HE 7456/1-1). T.J.S. is supported by the Deutsche Forschungsgemeinschaft (Jo 1324/1-1). H.Y.G. is supported by the National Research Foundation of Korea, Ministry of Science, ICT, and Future planning (2015R1D1A1A01056685) and faculty seed money from the Yonsei University College of Medicine (2015-32-0047). A.T.v.d.V. is supported by the DFG-fellowship (VE 196/1-1). We thank Yoko Chiba, Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, Yoko Tateda and Kiyotaka Kuroda for their technical assistance. This work was supported by grants (17ek0109151h0003 and 17ek0109278h0001) from Japan Agency for Medical Research and Development (AMED) to S.K. We acknowledge the support of the Biomedical Research Unit of Tohoku University Hospital and the Biomedical Research Core and the Institute for Animal Experimentation of Tohoku University Graduate School of Medicine. N.A.S is supported by the Egyptian Group for Orphan Renal Diseases (EGORD). M.A.J. is supported by Department of Science and Technology, Govt. of India (DST-SERB). M.Z. was supported by the Deutsche Forschungsgemeinschaft (SFB423)

Publisher Copyright:
© 2018 The Author(s).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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