Editors' ChoiceRenal disease

Stabilizing the Kidney’s Skeleton

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Science Translational Medicine  10 Aug 2011:
Vol. 3, Issue 95, pp. 95ec128
DOI: 10.1126/scitranslmed.3002999

Genetics is a family affair. Even though our understanding of complex polygenic disorders has recently benefited from studying large numbers of unrelated cases and controls, familial studies can be very powerful in single gene disorders: Linkage studies of familial conditions with even a small number of related individuals can be sufficient to implicate a genetic region. However, a classic problem with this technique is that the associated genetic interval can be large and contain many genes, and therefore it can be very difficult to determine which one is causal. In a recent study, Mele et al. (1) use familial linkage in combination with modern sequencing techniques to address this classical conundrum and identify gene variations that cause the human kidney disease focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis is a severe kidney disease that results in loss of protein in the urine and renal failure. Familial forms exist, and these familial cases are often severe and resistant to corticosteroid therapy. Fifty percent of the familial cases of this disease are not understood at a molecular level. Therefore, the authors studied members of a severely affected family in a genetic linkage study, which implicated a 16-megabase region containing 112 genes. To pick out the needle from this haystack, the authors used next-generation sequencing to identify previously unknown causal genetic variations within this region. A coding change polymorphism in a highly conserved region of the MYO1E gene (A159P) was discovered. MYO1E codes for a nonmuscle myosin protein expressed in podocyte cells, which contribute to the filtering mechanism in the glomerulus of the kidney. Functional studies revealed that this polymorphism resulted in abnormal cellular localization of Myo1E. The authors then sequenced this gene in 52 additional patients and found another coding change polymorphism (Y695X) in MYO1E in a second family; this polymorphism resulted in truncation of the protein.

Interestingly, these patients were resistant to glucocorticoid therapy, but had some response to cyclosporine. Recent data suggests that cyclosporine may stabilize the cytoskeleton in podocytes. Because Myo1E is a component of the podocyte cytoskeleton, it is intriguing to postulate that cyclosporine may directly address a molecular deficit related to the MYO1E variants and thus be a useful therapy for patients with this form of focal segmental glomerulosclerosis.

C. Mele et al., MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N. Engl. J. Med. 365, 295–306 (2011). [PubMed]

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