Identification and characterization of a new candidate gene for steroid resistant nephrotic syndrome

Nephrotic syndrome (NS) is characterized by consistent proteinuria, oedema, hypoalbuminemia, and it can be classified as steroid-sensitive (about 90%) or steroid-resistant (SRNS-about 10%). To date, mutations in at least 15 genes have been found to cause SRNS and although mutations in NPHS1 or NPHS2 are frequent causes of children SNSR, mutations in other genes are very rare. In addition, multiple allelism and heterogeneity together with a phenotypic clinical overlap require an extensive mutational analysis effort to identify the molecular aetiology. To identify SRNS by molecular diagnosis has important clinical implication, as this would prevent unnecessary administration of corticosteroids and immunosuppressants. We performed targeting and whole-exome (re)sequencing in 25 probands with a diagnosis of a paediatric SNSR (including 25 subjects steroid-sensitive). Because mutations in several genes have been demonstrated to lead to familial or sporadic SNSR, we focused our attention on these genes and on those candidates potentially implicated in the pathogenesis of the disorder. We identified a putative new candidate gene that may allow to define a novel clinical entity in the field of genetic disorders (hyperactivation of this gene was described to cause NS in podocyte-specific transgenic mice). Definition of the causative role of these mutations would represent the first case of an defect leading to a disorder where SRNS is part of a more complex clinical syndrome including also immunologic alterations. The results of our work may lead to the identification of a new causative gene for SRNS and provide definition of a previously unidentified clinical syndrome