Editorial Dystroglycan in the Molecular Diagnosis of the Podocytopathies Jeffrey B. Kopp Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland Clin J Am Soc Nephrol 4: 1696 –1698, 2009. doi: 10.2215/CJN.06910909 T he dystroglycan complex, among other molecular com- plexes, attaches podocytes to the glomerular basement membrane (GBM). Regele et al. (1) previously localized -dystroglycan and -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 -dystroglycan and by 50% for -dystroglycan, whereas expression of both dystroglcyans was normal or slightly in- creased 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 protein- uria). 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 -dystroglycan by podocytes, whereas -dystroglycan expres- sion was numerically but not significantly decreased. Dystroglycan assembles with other transmembrane and inter- cellular 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 -dystroglycan associates with dystrophin (in skeletal muscle and elsewhere) or with utrophin (in podocytes [7] and elsewhere). These molecules in turn interact with filamen- tous actin. Other members of the DGP include sarcoglycans, which are transmembrane proteins that interact with -dystrogly- can. Podocytes seem to express only -sarcoglycan (8). Two macromolecular complexes that tether podocytes to the glomerular basement membrane (GBM) have been identified: 31 integrins and dystroglycans (9). Dystroglycans were named on the basis of their role in muscular dystrophy but are widely distributed outside skeletal muscle. Dystroglycan is the product of a two-exon gene, DAG1, located on chromosome 3p21; posttrans- lational processing yields -dystroglycan and -dystroglycan, which maintain a noncovalent association. -Dystroglycan is an integral membrane protein. -Dystroglycan is located in the ex- tracellular space, extending into the lamina rara externa of the GBM. It has binding specificity for GBM components, including laminin and the agrin, the major heparan sulfate proteoglycan in GBM. Interestingly, exposure to reactive oxygen species deglyco- sylates -dystroglycan in vitro and thereby abrogates the ability of -dystroglycan to bind laminin and agrin, suggesting that carbo- hydrate residues may be required for these interactions (10). If this mechanism operates in vivo, then it would suggest a pathway by which reactive oxygen species might lead to podocyte loss. There remains controversy as to whether -dystroglycan is confined to the soles of the podocyte foot processes, as Regele et al. (1) sug- gested, or -dystroglycan expression extends to the apical do- main, as Berden and colleagues (11) found; the observed differ- ences may be due to differences in tissue preparation or antibody epitopes. What are the functions of dystroglycan and its partners in podocyte biology? First, together with 31 integrin, the DGP likely anchors the podocyte to the GBM, counteracting the expansible force of hydrostatic pressure within the glomerular capillary that could detach the podocyte. Second, podocytes may deploy dystroglycan to coordinate the spatial arrangement of particular GBM proteins, as suggested by Kojima and Ker- jaschki (8). Third, -dystroglycan contains sialic acid (as does podocalyxin) and, as noted already, -dystroglycan seems to be distributed in the apical podocyte domain. Thus, -dystrogly- can is positioned to help maintain podocyte foot process archi- tecture and in particular maintain the patency of the filtration slit. The removal of sialic acid with neuraminidase (sialidase) (12) and the failure to synthesize sialic acid in mice with a null mutation in the gene encoding the enzyme responsible for sialic acid (13) each is associated with foot process effacement and proteinuria, suggesting that sialic residues on -dystroglycan, podocalyxin, or other molecules, are critical to maintaining podocyte cytoarchitecture and the glomerular filtration barrier. Is there now a role for -dystroglycan immunostaining of kidney biopsies in clinical practice? A presentation of the semi- quantitative scoring of -dystroglycan staining carried out by Giannico et al. (2) is shown in Figure 2. Using a threshold score of 0.3 arbitrary units (which will of course vary from laboratory to laboratory and observer to observer), the sensitivity is 0.86, the specificity is 0.88, the positive predictive value is 0.67, and the negative predictive value is 0.95. Thus, in this series, re- duced -dystroglycan staining is modestly predictive of likely Published online ahead of print. Publication date available at www.cjasn.org. Correspondence: Dr. Jeffrey B. Kopp, 10 Center Drive, Room 3N116, NIH, Bethesda, MD 20892-1268. Phone: 301-594-3403; Fax: 301-402-0014; E-mail: jbkopp@nih.gov Copyright © 2009 by the American Society of Nephrology ISSN: 1555-9041/411–1696