Nephrotic syndrome (NS) results from disruption of the kidney filtration barrier and is associated with proteinuria, hypoalbuminemia, and edema. Many children with NS respond to steroid therapy; however, steroid-resistant NS (SRNS) progresses to end-stage disease that requires renal replacement therapy. In many cases, the underlying cause of SNRS is unknown; however, recent studies have identified monogenic mutations that underlie disease. Several proteins encoded by NS-associated genes localize to podocytes, which are essential for maintenance of the glomerular filtration barrier. Heon Yung Gee, Fujian Zhang, and colleagues at Harvard Medical School and Children’s National Medical Center evaluated families with NS and identified recessive mutations in the kidney ankyrin repeat-containing protein-encoding genes KANK1, KANK2, and KANK4. Additionally, an independent screen in a Drosophila model determined that the Drosophila KANK homologue (dKank) is required for nephrite function. KANK1, KANK2, and KANK4 all localized to podocytes, with KANK1 colocalizing with synaptopodin and KANK2 interacting with RHO GTPase regulator ARHGDIA, which is dysfunctional in some types of NS. Knock down of the KANK2 homologue in zebrafish induced an NS phenotype that is characterized by proteinuria and effacement of podocyte foot processes. The results of this study demonstrate that the KANK family of genes are evolutionarily conserved and required for maintenance of the glomerular filtration barrier. The accompanying transmission electron micrographs show the glomerular basement membrane (GBM) and podocyte foot processes in 5-day old control (left) and KANK2-deficent zebrafish. In control animals, foot processes are regularly spanned by slit diaphrams, while podocyte foot processes and the GBM are disorganized in KANK2-deficent animals.
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
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