Hildegard Zappel

Mutations 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 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.Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

ABSTRACT CDK10/CycM is a protein kinase deficient in STAR (toe Syndactyly, Telecanthus and Anogenital and Renal malformations) syndrome, which results from mutations in the X-linked FAM58A gene encoding Cyclin M. The biological functions of CDK10/CycM and etiology of STAR syndrome are poorly understood. Here, we report that deficiency of CDK10/Cyclin M promotes assembly and elongation of primary cilia. We establish that this reflects a key role for CDK10/Cyclin M in regulation of actin network organization, which is known to govern ciliogenesis. In an unbiased screen, we identified the RhoA-associated kinase PKN2 as a CDK10/CycM phosphorylation substrate. We establish that PKN2 is a bone fide regulator of ciliogenesis, acting in a similar manner to CDK10/CycM. We discovered that CDK10/Cyclin M binds and phosphorylates PKN2 on threonines 121 and 124, within PKN2′s core RhoA-binding domain. Furthermore, we demonstrate that deficiencies in CDK10/CycM or PKN2, or expression of a non-phosphorylatable version of PKN2, destabilize both the RhoA protein and the actin network architecture. Importantly, we established that ectopic expression of RhoA is sufficient to override the induction of ciliogenesis resulting from CDK10/CycM knockdown, indicating that RhoA regulation is critical for CDK10/CycMs negative effect on ciliogenesis. Finally, we show that kidney sections from a STAR patient display dilated renal tubules and abnormal, elongated cilia. Altogether, these results reveal CDK10/CycM as a key regulator of actin dynamics and a suppressor of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling. Moreover, they suggest that STAR syndrome is a ciliopathy.

Dextranomermikrosphären (Deflux) in der endoskopischen Therapie des vesikoureteralen Refluxes

ZusammenfassungFragestellung. Bisher gebräuchliche Substanzen in der endoskopischen Therapie des vesikoureteralen Refluxes wie Teflon, Silikon und bovines Kollagen sind hinsichtlich ihrer Biokompatibilität problematisch. Deshalb wurde der Einsatz von Dextranomermikrosphären (Deflux) untersucht. Methode und Patienten. Die endoskopische Therapie mit Deflux wurde bei 29 Kindern im Alter von 20 Monaten–13,5 Jahren durchgeführt (40 vesikoureterale Einheiten). Die Therapiekontrolle erfolgte durch Miktionszysturethrogramm nach 3–6 Monaten. Therapieergebnisse. Insgesamt war die endoskopische Refluxkorrektur bei 17 Kindern und 23 vesikoureteralen Einheiten erfolgreich. Ein infektassoziierter Reflux Grad I–III konnte bei 17 von 19 nachkontrollierten Kindern (89,5%) erfolgreich therapiert werden. Dagegen konnte bei Reflux Grad IV und V und bei Kindern mit neurogener Blasenentleerungsstörung kein dauerhafter Erfolg erzielt werden. Schlussfolgerung. Deflux stellt eine attraktive Therapiealternative in der endoskopischen Refluxtherapie dar. Insbesondere Kinder mit niedriggradigem, infektassoziiertem Reflux können von diesem minimalinvasiven Therapieansatz profitieren.AbstractPurpose. Substances currently used for endoscopic correction of vesicoureteric reflux like Teflon, silicone or bovine collagen are critical with regard to biocompatibility. We investigated dextranomer microspheres (Deflux) in the endoscopic therapy of vesicoureteric reflux. Methods and Patients. Deflux was used in 29 children aged 20 months to 13,5 years (40 vesicoureteric units). Effectiveness of treatment was controlled by voiding cystourethrography 3 to 6 months afterwards. Results. Overall, the endoscopic treatment with Deflux was successful in 17 children and 23 vesicoureteric units. Infection associated reflux I°–III° was treated successfully in 17 of 19 children (=89,5%). In contrast, endoscopic therapy was not effective in children with reflux IV° and V° and in children with neurogenic bladder dysfunction. Conclusion. Deflux is an attractive alternative in the endoscopic treatment of vesicoureteric reflux in children. Especially, children with infection associated low-grad reflux may profit from this minimally invasive therapy.