Editorial

MYO1E, Focal Segmental Glomerulosclerosis, and the Cytoskeleton

Julie R. Ingelfinger, M.D.

N Engl J Med 2011; 365:368-369July 28, 2011DOI: 10.1056/NEJMe1106093

Article

Focal segmental glomerulosclerosis, one of the most common glomerulopathies, is typically heralded by massive proteinuria, often associated with unremitting nephrotic syndrome and inexorable progression to end-stage kidney disease.1-3 Unfortunately, therapy is frequently unsuccessful — many patients with this disorder do not respond to treatment with glucocorticoids, and immunosuppressive therapy often fails as well. The disease also frequently recurs after kidney transplantation.

The podocyte is critical to the development of focal segmental glomerulosclerosis. This dynamic cell controls glomerular filtration by means of its slit-pore diaphragm and other properties, which include motility along the glomerular basement membrane.4 Podocytes surround and adhere to the glomerular capillary loops by means of cell-membrane receptors and have multiple extensions (foot processes) that interdigitate and adhere to one another, forming the slit diaphragm — a highly structured filtration barrier. Podocytes also help to maintain the integrity of the glomerular basement membrane and modulate the properties of capillary endothelial cells.

Although a small fraction of cases of focal segmental glomerulosclerosis are familial, unraveling the molecular basis of these cases has informed the biology of podocyte function.5 Over the past decade, mutations in nearly 20 different genes that affect multiple podocyte functions have been linked with focal segmental glomerulosclerosis.1,5 These include mutations in genes encoding proteins of the slit-diaphragm complex (NPHS1, which encodes nephrin; NPHS2, which encodes podocin; and CD2AP, which encodes CD2-associated protein) and in genes encoding proteins associated with the podocyte cell membrane (TRPC6, which encodes transient receptor potential cation channel 6; LAMB2, which encodes laminin β2; ITGB4, which encodes β4 integrin; CD151, which encodes tetraspanin CD151; and PLCE1, which encodes phospholipase C, epsilon 1, a membrane phospholipid catalyst), as well as mutations in a number of cytosolic genes encoding proteins that influence the podocyte cytoskeleton (ACTN4, which encodes alpha-actinin-4; MYH9, which encodes myosin heavy chain 9; and INF2, which encodes inverted formin 2). Mutations in APOL1, which encodes apolipoprotein L1, constitute a risk allele for focal segmental glomerulosclerosis in black patients and may be more important than MYH9 in that group. Furthermore, mutations in a number of nuclear and mitochondrial genes encoding proteins that influence podocyte function have also been reported, mainly in connection with syndromes in which focal segmental glomerulosclerosis may be seen (e.g., mutations in WT1, the Wilms' tumor 1 gene). Such discoveries have led to a far more complex classification of focal segmental glomerulosclerosis than was previously possible and, ultimately, should both elucidate interactions important to normal podocyte functioning and lead to novel treatments for glomerular diseases.

In this issue of the Journal, Mele et al.6 describe two families with focal segmental glomerulosclerosis and distinct mutations in MYO1E, a gene that encodes myosin 1E (a nonmuscle class I myosin), which is present in podocytes. The authors initially screened families with autosomal recessive focal segmental glomerulosclerosis with the use of whole-genome linkage analysis and high-throughput sequencing, and they identified a missense mutation in MYO1E in one family. Later, in another family, they identified another MYO1E mutation that results in protein truncation. All the affected patients were resistant to treatment with glucocorticoids, consistent with the course in most patients with focal segmental glomerulosclerosis, yet most of them responded to cyclosporine, a calcineurin inhibitor. Cyclosporine is known to cause remission in some patients with focal segmental glomerulosclerosis, but the mechanism underlying such remission has remained elusive. Recently, it has been suggested that cyclosporine may act by stabilizing the cytoskeleton, which may make sense, considering the functions of MYO1E that are disrupted by the reported mutations; the report by Mele et al. suggests that this may be the case.

Wild-type Myo1E is a membrane-associated class I myosin with a motor-head domain that binds ATP and F-actin, a calmodulin-binding neck domain, and a tail domain. One of the new mutations results in an A159P substitution that changes the localization of Myo1E, which is normally membrane-bound, to the cytoplasm. The other mutation, c.2085T→G, causes an interruption of the protein at the beginning of the calmodulin-binding domain. Although the wild-type MYO1E protein colocalizes with CD2-associated protein, which is involved in cytoskeletal remodeling and in the slit-pore diaphragm mechanism, such colocalization does not occur with the abnormal protein.

MYO1E appears to be important for podocyte motility and may also stabilize the podocyte cytoskeleton. Aberrant MYO1E protein, however, seems to lack this latter property. There is evidence that cyclosporine may stabilize the actin cytoskeleton of the podocyte by blocking calcineurin-induced synaptopodin dephosphorylation.7 Thus, cyclosporine may help overcome the cytoskeletal abnormalities that are induced by the abnormal MYO1E protein. Perhaps cytoskeletal stabilization occurs in response to other agents that are effective in some patients with focal segmental glomerulosclerosis. For example, another agent that has recently been observed to be useful in this disorder is rituximab, an anti-CD20 monoclonal antibody, which also stabilizes the podocyte actin cytoskeleton,8 perhaps acting by means of sphingomyelin phosphodiesterase, acid-like 3b (SMPDL-3b), acid sphingomyelinase (ASMase), and cytoskeletal remodeling. Furthermore, stimulation of the calcium-sensing receptor may have effects on the podocyte cytoskeleton and, in experimental models of glomerulosclerosis, appears to ameliorate the disease. Glucocorticoids increase actin polymerization by means of RhoA, a guanosine triphosphatase,9 and heat-shock protein 27 (Hsp27).10 Thus, the behavior of the abnormal MYO1E protein may provide a hint as to why agents that stabilize the podocyte cytoskeleton are important to the successful therapy of focal segmental glomerulosclerosis.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMe1106093) was published on July 13, 2011, and updated on August 24, 2011, at NEJM.org.

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Citing Articles (2)

Citing Articles

1. 1

   Imed Helal, Godela M. Fick-Brosnahan, Berenice Reed-Gitomer, Robert W. Schrier. (2012) Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nature Reviews Nephrology 8:5, 293-300
   

2. 2

   Aihua Zhang, Songming Huang. (2012) Progress in Pathogenesis of Proteinuria. International Journal of Nephrology 2012, 1-14