期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04193-w
关键词
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资金
- National Institutes of Health [DK076683]
- Howard Hughes Medical Institute
- German National Academy of Sciences Leopoldina [LPDS-2015-07]
- ASN Foundation for Kidney Research
- DFG-fellowship [HE 7456/1-1, VE 196/1-1]
- Deutsche Forschungsgemeinschaft [Jo 1324/1-1, SFB423]
- National Research Foundation of Korea, Ministry of Science, ICT, and Future planning [2015R1D1A1A01056685]
- Yonsei University College of Medicine [2015-32-0047]
- Japan Agency for Medical Research and Development (AMED) [17ek0109151h0003, 17ek0109278h0001]
- Biomedical Research Unit of Tohoku University Hospital
- Biomedical Research Core of Tohoku University Graduate School of Medicine
- Institute for Animal Experimentation of Tohoku University Graduate School of Medicine
- Egyptian Group for Orphan Renal Diseases (EGORD)
- Department of Science and Technology, Govt. of India (DST-SERB)
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.
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