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

First Author  Ashraf S Year  2018
Journal  Nat Commun Volume  9
Issue  1 Pages  1960
PubMed ID  29773874 Mgi Jnum  J:262845
Mgi Id  MGI:6161131 Doi  10.1038/s41467-018-04193-w
Citation  Ashraf S, et al. (2018) Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun 9(1):1960
abstractText  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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