biostudies-literatureAshraf SNIDDK NIH HHSNIH HHS1960https://www.ebi.ac.uk/biostudies/studies/S-EPMC5958119biostudies-literatureUnknown9(1)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 guanineNature communicationsMutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment.PMC5958119T32 DK007726R01 DK103022S10 OD030363R01 DK076683S10 OD018521P30 DK079310T32 DK007757Soliman NAHildebrandt FKumar ASKumagai NRakhmetova ADaga AGupta ABvan der Ven ATKaufman LKure SSchmidt JMWassmer SRJalalah SRao JJairajpuri MAWidmeier EZenker MShril SJungraithmayr TSchanze DMane SMBraun DALow BCKikuchi ALawson JATan WPei YBogdanovic RIijima KFehrenbach HTakizawa TSadowski CEWarejko JKEl Desoky SZappel HMajmundar AJNiihori TLowy DRGee HYStajic NStrehlau JTanaka RSchapiro DAoki YNakayama KWong JBagga AHermle TAirik MKaito HTsukaguchi HKudo HNozu KLovric SFunayama RHamahira KAshraf SCampbell KMetcalfe KKobayashi YJobst-Schwan TKari JAPabst WLTripathi BKLifton RPfalseMutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment.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 guanine2018-01-01T00:00:00Z2018 May2026-05-03T23:18:39.223Z2019-03-26T23:38:05ZS-EPMC59581192977387410.1038/s41467-018-04193-w