[HTML][HTML] KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

HY Gee, F Zhang, S Ashraf, S Kohl… - The Journal of …, 2015 - Am Soc Clin Investig
HY Gee, F Zhang, S Ashraf, S Kohl, CE Sadowski, V Vega-Warner, W Zhou, S Lovric
The Journal of clinical investigation, 2015Am Soc Clin Investig
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
k idney ank yrin repeat-containing protein 1 (KANK1), KANK2, and KANK4 in individuals
with nephrotic syndrome. In an independent functional genetic screen of Drosophila cardiac …
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 GTP-bound 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.
The Journal of Clinical Investigation