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KANK deficiency leads to podocyte dysfunction and nephrotic syndrome.

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.

Pubmed ID: 25961457 RIS Download

Mesh terms: Animals | Cell Line | Drosophila Proteins | Drosophila melanogaster | Female | Gene Knockdown Techniques | Humans | Male | Microfilament Proteins | Mutation | Nephrotic Syndrome | Podocytes | Proteinuria | Rats | Tumor Suppressor Proteins | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: NHLBI NIH HHS, Id: HL090801
  • Agency: NIDDK NIH HHS, Id: DK091405
  • Agency: NIDDK NIH HHS, Id: DK076683
  • Agency: NIDDK NIH HHS, Id: RC1 DK086542
  • Agency: NIDDK NIH HHS, Id: P30 DK079310
  • Agency: NIDDK NIH HHS, Id: R01 DK076683
  • Agency: NIDDK NIH HHS, Id: R01 DK098410
  • Agency: NIDDK NIH HHS, Id: R00 DK091405
  • Agency: NHLBI NIH HHS, Id: R01 HL090801
  • Agency: Howard Hughes Medical Institute, Id: DK086542
  • Agency: NIDDK NIH HHS, Id: DK098410
  • Agency: NIDDK NIH HHS, Id: K99 DK091405
  • Agency: NIDDK NIH HHS, Id:

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