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Identification of BRAF as a new interactor of PLC1, the protein mutated in nephrotic syndrome type 3

Departments of ¹Pediatrics, ²Internal Medicine, and ³Human Genetics, University of Michigan, Ann Arbor, Michigan

Submitted 24 July 2007 ; accepted in final form 10 October 2007

Steroid-resistant nephrotic syndrome is a malfunction of the kidney glomerular filter that leads to proteinuria, hypoalbuminemia, edema, and renal failure. Recently, we identified recessive mutations in the phospholipase C epsilon 1 gene (PLCE1) as a new cause of early-onset nephrotic syndrome and demonstrated interaction of PLC1 with IQGAP1. To further elucidate the mechanism by which PLCE1 mutations cause nephrotic syndrome, we sought to identify new protein interaction partners of PLC1. We utilized information from the genetic interaction network of C. elegans. It relates the PLCE1 ortholog (plc-1) to the C. elegans ortholog (lin-45) of human BRAF (v-raf murine sarcoma viral oncogene homolog B1). We hypothesized that this may indicate a functional protein-protein interaction. Using GST pull down of HEK293T cell lysates in vitro and coimmunoprecipation of mouse kidney lysates in vivo, we show that BRAF interacts with PLC1. By immunohistochemistry in rat kidney, we demonstrate that both proteins are coexpressed and colocalize in developing and mature glomerular podocytes, reporting for the first time the expression of BRAF in the glomerular podocyte.

glomerulus; immunocytochemistry