Focal segmental glomerulosclerosis (FSGS) of childhood is an increasingly prevalent disease that manifests as steroid resistant nephrotic syndrome (SRNS) and leads to end stage kidney disease. The disease severely interferes with psychosocial development of affected children. Since the pathogenesis of this disease group is largely unknown, treatment options are limited and controversial. Treatment of these patients with multiple immunosuppressive and cytotoxic agents brings about considerable morbidity and mortality. Recent breakthroughs in understanding the pathogenesis of childhood FSGS have come from positional cloning of novel genes (NPHS1/nephrin, NPHS2/podocin, LAMB2, and others) that are mutated in children with FSGS and congenital nephrotic syndrome. These findings demonstrated that recessive mutations in a single gene are sufficient to cause FSGS. This offers the opportunity to develop new approaches towards treatment and prevention based on understanding the molecular pathogenesis of these conditions. Towards this goal we have made the following progress: First, we showed that mutations in NPHS2 are a frequent cause of FSGS, accounting for 28% of all childhood cases, and that 66% of all SRNS cases in the first year of life can be explained by mutations in four genes only. We performed mutational analysis in >1,300 individuals from a worldwide cohort and detected the genotype-phenotype correlation that all children with two NPHS2 mutations are steroid resistant, but have a reduced risk for FSGS recurrence in a kidney transplant. Second, since first submission, we identified the gene that we mapped to the SRN3 locus using positional cloning and a new candidate gene selection strategy, by showing that mutations in the PLCE1 gene (phospholipase C epsilon) are a new cause of recessive early-onset nephrotic syndrome. Depending on the type of mutation, children have either the histologic picture of diffuse mesangial sclerosis (DMS) or of FSGS. Remarkably, some patients responded to steroid or cyclosporine A treatment. We thereby identified the first gene ever described in steroid sensitive nephrotic syndrome. We characterized the pathogenic role of PLCel by demonstrating its role for nephrin and podocin expression in glomerular development, and detected an interaction with the glomerular protein IQGAP1. We generated a zebrafish model for this disease, which will be useful for therapeutic studies. Third, we have mapped two new gene loci (SRN2 and SRN4) for recessive FSGS on chromosomes 14q24.3 and 13q, respectively. On the basis of these preliminary data we intend to: 1) Identify and functionally characterize a new gene (SRN2) that causes FSGS/SRNS. 2) Expand functional studies on the disease mechanisms of PLCE1 mutations as a newly discovered cause of SRNS/SSNS. 3) Identify by positional cloning and functionally characterize the SRN4 gene and map additional loci. As shown for PLCE1/SRN3 mutations, these studies will generate new insights into the molecular basis of childhood FSGS, will provide useful biomarkers for translation of genetic findings into clinical applications, and will help develop animal models for drug testing in nephrotic syndrome.
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