Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of progressive renal function decline and affects millions of people. In a recent study, 30% of SRNS cases evaluated were the result of monogenic mutations in 1 of 27 different genes. Here, using homozygosity mapping and whole-exome sequencing, we identified recessive mutations in kidney ankyrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac nephrocytes, which are equivalents of mammalian podocytes, we determined that the Drosophila KANK homolog (dKank) is essential for nephrocyte function. RNAi-mediated knockdown of dKank in nephrocytes disrupted slit diaphragm filtration structures and lacuna channel structures. In rats, KANK1, KANK2, and KANK4 all localized to podocytes in glomeruli, and KANK1 partially colocalized with synaptopodin. Knockdown of kank2 in zebrafish recapitulated a nephrotic syndrome phenotype, resulting in proteinuria and podocyte foot process effacement. In rat glomeruli and cultured human podocytes, KANK2 interacted with ARHGDIA, a known regulator of RHO GTPases in podocytes that is dysfunctional in some types of nephrotic syndrome. Knockdown of KANK2 in cultured podocytes increased active GTPbound RHOA and decreased migration. Together, these data suggest that KANK family genes play evolutionarily conserved roles in podocyte function, likely through regulating RHO GTPase signaling.
Bibliographical noteFunding Information:
The authors thank the families who contributed to this study. We thank the Bloomington stock center and the Vienna Drosophila Resource Center for fly stocks. This research was supported by grants from the NIH to F. Hildebrandt (DK076683 and DK086542), to W. Zhou (DK091405), and to Z. Han (DK098410 and HL090801). F. Hildebrandt was supported by the NephCure Foundation. H.Y. Gee is supported by a American Society of Nephrology Nephcure Foundation for Kidney Research grant. W. Zhou is a Carl W. Gottschalk Scholar. F. Hildebrandt is an investigator of the Howard Hughes Medical Institute and an associate of the Manton Center.
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