ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption
Shazia Ashraf, … , Corinne Antignac, Friedhelm Hildebrandt
Shazia Ashraf, … , Corinne Antignac, Friedhelm Hildebrandt
Published November 25, 2013
Citation Information: J Clin Invest. 2013;123(12):5179-5189. https://doi.org/10.1172/JCI69000.
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Research Article

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

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.

Authors

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

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Figure 5

CoQ10 content in EBV-transformed lymphoblasts and fibroblasts from SRNS families with mutations in ADCK4.

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CoQ10 content in EBV-transformed lymphoblasts and fibroblasts from SRNS ...
(A) Scatter plot showing the total CoQ10 content in EBV-transformed lymphoblasts derived from either healthy or affected individuals from the A2338 and A4169 families. Individuals A2338-21, A2338-22, and A4169-21 are affected with SRNS, while A2338-26 and A2338-27 have both wild-type alleles. The content of CoQ10 is presented with the average ± SD denoted by 3 horizontal lines (n = 4; except n = 6 for A4169-21). The content from A2338-26 is significantly higher than the CoQ10 content from A2338-21, A2338-22, and A4169-21 (multiple comparison, P < 0.0001). Symbols indicate individual lymphoblasts; horizontal bars indicate the average. (B) Scatter plot showing the total CoQ10 content in fibroblasts derived from either healthy parents or affected individuals (Pt5496 and Pt5497). The content of CoQ10 is presented with the average ± SD denoted by 3 horizontal lines (n = 8). CoQ10 content from #50551 is statistically lower than CoQ10 content from #50550 (multiple comparison, P = 0.0134) and significantly higher than the CoQ10 contents from #50552 and #50553 (multiple comparison, P < 0.0001). Symbols indicate individual fibroblasts; horizontal bars indicate the average. (C) In vivo maximal uncoupled OCR over the whole respiratory chain, including the Q10 transfer of electrons from mitochondrial complex I and complex II to complex III. Maximal respiration was significantly reduced in fibroblasts from Pt5496 and Pt5497 compared with that in control fibroblasts. Data shown are mean ± SD (n > 10). *P < 0.001.