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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.

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