KANK deficiency leads to podocyte dysfunction and nephrotic syndrome
Heon Yung Gee, … , Zhe Han, Friedhelm Hildebrandt
Heon Yung Gee, … , Zhe Han, Friedhelm Hildebrandt
Published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2375-2384. https://doi.org/10.1172/JCI79504.
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Research Article Nephrology

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Abstract

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.

Authors

Heon Yung Gee, Fujian Zhang, Shazia Ashraf, Stefan Kohl, Carolin E. Sadowski, Virginia Vega-Warner, Weibin Zhou, Svjetlana Lovric, Humphrey Fang, Margaret Nettleton, Jun-yi Zhu, Julia Hoefele, Lutz T. Weber, Ludmila Podracka, Andrej Boor, Henry Fehrenbach, Jeffrey W. Innis, Joseph Washburn, Shawn Levy, Richard P. Lifton, Edgar A. Otto, Zhe Han, Friedhelm Hildebrandt

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Figure 1

HM and WES identify genetic variants in the KANK1, KANK2, and KANK4 genes in families with NS.

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HM and WES identify genetic variants in the KANK1, KANK2, and KANK4 gene...
(A, C, and E) Nonparametric lod scores (NPL) are plotted across the human genome. The x axis shows SNP marker positions on human chromosomes concatenated from p-ter (left) to q-ter (right). Genetic distance is given in cM. Maximum nonparametric lod score peaks indicate candidate regions of homozygosity by descent. (B, D, and F) Gene symbol (underlined), family number, variant, and predicted translational changes are given. Sequence traces are shown for the variant above normal control. Mutated nucleotides are indicated by arrowheads. (A) HM of an individual (A982-21) with SSNS. KANK2 is positioned (arrowhead) on chromosome 19 within one of the homozygous candidate regions. (B) Chromatogram of a KANK2 mutation identified in a family (A982) with SSNS (see also Table 1). (C) HM of an individual (A1389-21) with SSNS. KANK1 is positioned (arrowhead) on chromosome 9. (D) Chromatogram of a KANK1 variant identified in family A1389 (see also Table 1). (E) HM of an individual (A1436-24) with SRNS. KANK4 is positioned (arrowhead) with a homozygous region on chromosome 1. (F) Chromatogram of a KANK4 variant identified in family A1436 (see also Table 1).