ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption

J Clin Invest. 2013 Dec;123(12):5179-89. doi: 10.1172/JCI69000.

Shazia Ashraf, Heon Yung Gee, Stephanie Woerner, Letian X Xie, Virginia Vega-Warner, Svjetlana Lovric, Humphrey Fang, Xuewen Song, Daniel C Cattran, Carmen Avila-Casado, Andrew D Paterson, Patrick Nitschké, Christine Bole-Feysot, Pierre Cochat, Julian Esteve-Rudd, Birgit Haberberger, Susan J Allen, Weibin Zhou, Rannar Airik, Edgar A Otto, Moumita Barua, Mohamed H Al-Hamed, Jameela A Kari, Jonathan Evans, Agnieszka Bierzynska, Moin A Saleem, Detlef Böckenhauer, Robert Kleta, Sherif El Desoky, Duygu O Hacihamdioglu, Faysal Gok, Joseph Washburn, Roger C Wiggins, Murim Choi, Richard P Lifton, Shawn Levy, Zhe Han, Leonardo Salviati, Holger Prokisch, David S Williams, Martin Pollak, Catherine F Clarke, York Pei, Corinne Antignac, Friedhelm Hildebrandt

PMID: 24270420 DOI: 10.1172/JCI69000

Abstract

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory Enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or Other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

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