Dystroglycan in the Molecular Diagnosis of the Podocytopathies

Abstract

The dystroglycan complex, among other molecular complexes, attaches podocytes to the glomerular basement membrane (GBM). Regele et al. (1) previously localized α-dystroglycan and β-dystroglycan to the sole of the podocyte foot process. Furthermore, they found that in minimal-change nephropathy (MCN), protein expression was reduced by 75% for α-dystroglycan and by 50% for β-dystroglycan, whereas expression of both dystroglcyans was normal or slightly increased in FSGS. In this issue of CJASN , Giannico et al. (2) extend these findings to a somewhat different clinical setting, namely, seven patients with findings typical of MCN, including extensive foot process effacement and nephrotic proteinuria (with the exception that one patient had subnephrotic proteinuria). Because of limitations in the number of glomeruli present on these biopsies, the diagnosis of unsampled FSGS could not be safely excluded, and this group is therefore described as “undefined.” Giannico et al. report decreased expression of α-dystroglycan by podocytes, whereas β-dystroglycan expression was numerically but not significantly decreased. Dystroglycan assembles with other transmembrane and intercellular proteins to form the dystroglycan glycoprotein complex (DGP; Figure 1). DGPs are expressed in most, if not all, tissues (recent reviews are available [3–5]) and are expressed by kidney cells, including podocytes and tubular epithelial cells (6). The C-terminal domain of β-dystroglycan associates with dystrophin (in skeletal muscle and elsewhere) or with utrophin (in podocytes [(7)] and elsewhere). These molecules in turn interact with filamentous actin. Other members of the DGP include sarcoglycans, which are transmembrane proteins that interact with β-dystroglycan. Podocytes seem to express only δ-sarcoglycan (8). Figure 1. The dystroglycan complex of the podocyte. β-Dystroglycan is an integral plasma membrane protein; it is noncovalently associated with α-dystroglycan (shown with its glycan side chains), which extends into the lamina rara externa of the …