Denys-Drash syndrome is a rare disorder of urogenital development characterized by the association of early onset glomerulopathy caused by diffuse mesangial sclerosis, gonadal dysgenesis leading to pseudohermaphroditism in males, and a high risk of developing Wilms' tumor. The syndrome is caused by dominant negative point mutations in the WT1 gene that encodes a tumor suppressor transcription factor normally expressed in podocytes. Mutations usually affect the zinc fingers of the WT1 protein. The basic defect is unknown in most cases of isolated diffuse mesangial sclerosis, a disease characterized by the same glomerular changes as in Denys-Drash syndrome but possibly transmitted as an autosomal recessive trait. Here we show that the distribution of WT1 is abnormal in most patients with Denys-Drash syndrome : WT1 nuclear staining of podocytes is decreased or absent. This finding is consistent with the decreased DNA binding capacity of the mutated protein. One target gene of WT1 is PAX2, the expression of which is down-regulated in podocytes during early stages of nephrogenesis. We demonstrate that WT1 mislocalization is associated with abnormal podocyte expression of PAX2 protein and RNA. We suggest that persistent expression of PAX2 is likely to result from the loss of WT1 dependent transcriptional repression and may participate in the pathological mechanisms leading to glomerular dysfunction. Abnormal distribution of WT1 and PAX2 was also observed in isolated diffuse mesangial sclerosis suggesting that a defect in WT1 could also be operative in isolated diffuse mesangial sclerosis. Primary involvement of PAX2 is an alternative hypothesis because persistent expression of PAX2 in transgenic mice is associated with the occurrence of early and severe glomerulopathy.