Dysregulation of WTI (−KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation

Mutations in the LIM homeobox transcription factor 1-beta (LMX1B) are a cause of nail patellar syndrome, a condition characterized by skeletal changes, glaucoma and focal segmental glomerulosclerosis. Recently, a missense mutation (R246Q) in LMX1B was reported as a cause of glomerular pathologies without extra-renal manifestations, otherwise known as nail patella-like renal disease (NPLRD). We have identified two additional NPLRD families with the R246Q mutation, though the mechanisms by which LMX1B(R246Q) causes a renal-specific phenotype is unknown. In this study, using human podocyte cell lines overexpressing either myc-LMX1B(WT) or myc-LMX1B(R246Q), we observed dominant negative and haploinsufficiency effects of the mutation on the expression of podocyte genes such as NPHS1, GLEPP1, and WT1. Specifically, we observed a novel LMX1B(R246Q)-mediated downregulation of WT1(−KTS) isoforms in podocytes. In conclusion, we have shown that the renal-specific phenotype associated with the LMX1B(R246Q) mutation may be due to a dominant negative effect on WT1(−KTS) isoforms that may cause a disruption of the WT1 (−KTS):(+KTS) isoform ratio and a decrease in the expression of podocyte genes. Full delineation of the LMX1B gene regulon is needed to define its role in maintenance of glomerular filtration barrier integrity.