Nephrotic syndrome is a pathologic entity characterized by massive loss of protein in the urine, hypoalbuminemia, and edema. It constitutes one of the most common diagnoses made in pediatric nephrology (1). About 90% of all children with sporadic nephrotic syndrome, meaning nephrotic syndrome not associated with a positive family history, respond to steroid treatment (2). Unfortunately, the remaining steroid-resistant patients are at high risk for adverse effects of the required invasive drug therapy and prone to develop progressive disease, and renal failure. End-stage renal disease, requiring dialysis or transplantation therapy, occurs in a large number of these patients which places an enormous burden on these children and poses a huge challenge for the caring physicians and families (3). Thus, it comes as no surprise that the recent identification of genes involved in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS) has generated a great deal of interest. It is now clear that mutations in genes encoding for proteins of the podocyte, the visceral epithelial cell of the kidney glomerulus, can cause nephrotic syndrome (4). NPHS1, encoding the podocyte protein nephrin, has been identified as the responsible gene in congenital nephrotic syndrome of the Finnish type (5). Podocin (6), α-actinin-4 (7), TRPC6 (8,9), and CD2AP (10) are all components of the podocyte foot processes that have been discovered subsequently through genetic approaches. Mutations in these genes cause focal-segmental glomerulosclerosis and proteinuria resistant to the treatment with corticosteroids. In fact, it is now getting clear that a majority of SRNS cases may have a genetic basis. I.e., mutations in the podocin-coding gene NPHS2 account for about 20% of cases with sporadic SRNS (11–14).

Mutations in the Wilms' tumor predisposing gene WT1 now join NPHS2 as an important gene involved in the pathogenesis of sporadic SRNS. The study by Mucha and the APN investigators in this issue together with previous work from the same investigators shows that mutations in WT1 account for sporadic SRNS in almost 10% of cases (15,16). WT1, the first gene found to be inactivated in Wilms' tumor, or nephroblastoma (17) encodes a zinc finger transcription factor that functions both as tumor suppressor (18) and as critical regulator of kidney and gonad development (19). This protein is expressed in a tightly regulated pattern within the embryonic kidney and is essential for renal development in mice (20). Germline deletions or mutations of WT1 have been linked to WAGR (Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation) syndrome (21,22), Drash syndrome (23) and Frasier syndrome (24). Mucha et al. now show that WT1 mutations also have to be considered in patients with sporadic, nonsyndromic SRNS (15). All mutations in this study localized to exons 8 and 9 of WT1 and patients with WT1-associated SRNS predominantly displayed primary focal and segmental glomerulosclerosis on kidney biopsy.

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