Unexpected role of TRPC6 channel in familial nephrotic syndrome: does it have clinical implications?

F ocal and segmental glomerulosclerosis (FSGS) is a leading cause of glomerulonephritis and chronic kidney disease (CKD) in children and young adults (1). As much as one fifth of the ESRD population carries this diagnosis, and the proportion of ESRD attributed to FSGS has increased more than 10-fold over the past two decades (2). The glomerular landmarks of FSGS can develop secondary to a variety of systemic conditions, including disorders that cause chronic hypoxemia, processes that augment glomerular blood flow, and diseases that reduce renal mass. The structural features of FSGS also develop in patients who lack recognized systemic diseases, so-called primary (or idiopathic) FSGS. Over the past three decades, the recognition of familial forms of FSGS has grown, and this information has been highlighted in recent years with characterization of several human genes that cause FSGS (3). Most recently, a mutation in a member of the canonical transient receptor potential (TRP) family of proteins, TRPC6, was identified to cause FSGS in a large kindred of autosomal dominant FSGS (4). The mutation in TRPC6, in contrast to genes that have been implicated in the pathogenesis of FSGS, seems to perturb cytosolic calcium ([Ca ]i) signaling. The purpose of this review is to examine what is known about TRPC6 mutations in familial nephrotic syndrome and to explore how this new knowledge may be applied to the care of patients with glomerular diseases.