C hronic kidney disease (CKD) affects more than 10% of people worldwide. 1 Renal fibrosis is the common endpoint of most CKD. 2 Therefore, preventing or
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.
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 0 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/CycM's 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.
Background HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. Methods Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. Results Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of − 0.33 ml/min/ 1.73m 2 per year (± 8.9). In patients with an increase in cyst number, the annual GFR reduction was − 2.8 ml/min/1.73m 2 (± 13.2), in the total cohort − 1.0 ml/min/1.73m 2 (±10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged Electronic supplementary material The online version of this article (
Off-label drug use in paediatrics is associated with an increased risk of adverse drug reactions. Any risk–benefit analysis has to be based on value judgments that should include parents' views. However, nothing is known so far about the parents' perspective on this critical issue. Therefore, a quantitative survey with parents of healthy and chronically ill children was carried out (n = 94). Knowledge about the practise of off-label use is generally poor in both groups. Surprisingly, this is also true for the parents of children with chronic disease. Nine percent of the parents of chronically ill children and 20% of the parents of healthy children would refuse treatment with an off-label drug. Parents who have poor knowledge about the practise of off-label use tend to refuse to volunteer their child for study participation. Therefore, the information of parents on the off-label use of drugs is important to meet ethical standards and to increase the parents' acceptance of medical studies with children.
Juvenile systemic lupus erythematosus is a rare multisystemic autoimmune disease with variable clinical manifestations, and disease onset before 16 years of age. Patients younger than 5 years are rarely affected and the age of onset may contribute to the course of disease in terms of clinical presentation, organ involvement, and serological findings. Here, we report two exemplary early-onset SLE patients, a 28-month-old patient with WHO class IIB kidney disease, arthritis, and a typical antibody constellation and an 11-month-old infant that presented with microcytic anemia, leukocytosis, arthritis, fasciitis, fatty liver disease, protein losing enteropathy, edema, and minimal change glomerulonephritis. Epidemiologic and clinical features of early-onset SLE compared to other forms of SLE are given and differential diagnoses and treatment options are discussed.
Neonatal-onset multisystem inflammatory disease (NOMID) is due to mutations in the CIAS1 gene. We describe the case of a 5-year-old boy with neonatal onset of urticaria-like rash, chronic fever, laboratory findings of systemic inflammation, hepatosplenomegaly, and chronic CNS inflammation associated with sensorineural deafness. Sequence analysis of exon 3 of the CIAS1 gene revealed a novel C1754A/S331R mutation. Since experimental evidence suggests that patients with cryopyrin-associated periodic syndromes (CAPS) could respond to inhibition of binding of interleukin IL-1alpha and IL-1beta to the IL-1 receptor type 1, we treated the child with the IL-1 receptor antagonist anakinra. A remarkable clinical and serological response to therapy was observed, suggesting that pharmacological inhibition of the IL-1 signaling pathway offers an important new treatment option for patients with NOMID.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.