Introduction Tubular dysfunction is usually characteristic of Dents disease; however, focal segmental glomerulosclerosis (FSGS) can also be present. resulted in defective transferrin endocytosis and was associated with decreased cell proliferation and increased cell migration, which are hallmarks of podocyte injury. Conclusions The mutation, which causes Dents disease, may be associated with FSGS without hyercalcuria and nepthrolithiasis. The present findings supported the hypothesis that CLCN5 participates in protein trafficking in podocytes and plays a critical role in organizing the components of the podocyte slit GW-786034 manufacturer diaphragm to help maintain normal cell physiology and a functional filtration barrier. In addition to tubular dysfunction, mutations in may also lead to podocyte dysfunction, GW-786034 manufacturer which results in a histologic picture of FSGS that may be a primary event and not a consequence of tubular damage. mutations have been reported in patients with Dents disease.2, 3, 4 The gene encodes a chloride and/or proton exchanger that plays an important role in endosomal acidification and receptor-mediated endocytosis. The protein has 18 -helices (A?R). More than 40% of mutations seen in Dents disease have been found in O and P helices.5 The clinical GW-786034 manufacturer presentation of Dents disease may be deceptive, with a substantial number of patients expressing a partial or atypical phenotype,6 which causes difficulty in its diagnosis.2 Many patients may not have classical features (e.g., rickets, nephrocalcinosis, or nephrolithiasis) but may only have severe proteinuria, which consists of mostly low-molecular-weight proteins without high-grade albuminuria. On initial presentation, this high-grade proteinuria may be confused for nephrotic range proteinuria in patients with primary FSGS, when in fact, the underlying etiology is usually Dents disease; therefore, careful clinical evaluation is essential. Although Dents disease is largely considered a tubular disease,7 FSGS, or more commonly, focal global glomerulosclerosis (FGGS), may be seen as a dominant feature in some patients with Dents disease.7, 8 In GW-786034 manufacturer the kidney, is expressed in proximal tubules, thick ascending limbs, and -intercalated cells of the collecting duct.9 The protein functions as a 2 Cl?/H+ exchanger and is involved in the acidification of endosomes, processing, and degradation of absorbed proteins, and megalin-dependent absorption of proteins. The expression of in glomerular cells has not been well-documented. Therefore, it is intriguing that this glomerular pathology is usually caused by a variant of a tubular protein. A key aspect of primary FSGS pathogenesis is usually podocyte damage and loss.10, 11 Mutations in genes that encode glomerular proteins, particularly in visceral epithelial cells (podocytes), lead to the development of FSGS.12 Previous reports have suggested that primary tubular injury may lead to glomerular sclerosis by mechanisms that are not yet understood.13, 14 In this study, we show that a variant of is present in a family with FSGS, and that is expressed in human podocytes and may play a role in glomerular physiology and pathology. Based on our results, we hypothesize that FSGS lesions, which are observed in patients with Dents disease, result from altered localization and/or function of in the podocytes, and are not purely a secondary consequence of tubular injury. This novel mutation has provided a unique opportunity to explore the mechanism by which the 2 2 Cl?/H+ exchanger functions in podocytes. Materials and 4E-BP1 Methods The study was approved by the Medical University of South Carolina (MUSC) Institutional Review Board, and signed informed consent was obtained from all study participants. Urine calcium was measured using Abbott Architect analyzer (Abbott Park, IL) at the MUSC central laboratory, and urine 2-microglobulin GW-786034 manufacturer at the ARUP Laboratory (Salt Lake City, Utah) using a quantitative chemiluminescent immunoassay. Whole blood was collected from affected and unaffected family members in.