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 1

HM and exon capture resequencing reveal ADCK4 mutations as causes of SRNS.

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HM and exon capture resequencing reveal ADCK4 mutations as causes of SRN...
(A) Renal histology of individual A2338-21 reveals global glomerulosclerosis by excess PAS staining (red). Original magnification, ×200. (B) Renal histology of individual Pt5496 shows cFSGS. PAS staining (left) reveals retraction and collapse of the capillary tuft, with numerous foam cells and groups of hyperplastic and vacuolated visceral epithelial cells. Original magnification, ×40. Electron microscopy image (right) shows foot process effacement (black arrowheads). In addition, capillary basement membranes are thickened and remodeled. Original magnification, ×15,000. (C) Nonparametric LOD (log of the odds ratio) (NPL) score profile across the human genome in 2 siblings with SRNS of consanguineous family A2338. Five maximum NPL peaks (red circles) indicate candidate regions of homozygosity by descent. ADCK4 is positioned (arrowhead) within a peak on chromosome (Chr) 19. Numbers at the bottom of the panels are measured in centimorgan (cM). (D) Exon structure of human ADCK4 cDNA. ADCK4 contains 15 exons. Positions of start codon (ATG) and of stop codon (TGA) are indicated. (E) Domain structure of ADCK4. The helical, ABC1, and kinase domains are depicted by colored bars in relation to encoding exon position. (F) Eleven different ADCK4 mutations in eight families with SRNS. Family numbers and amino acid changes (Table 1) are given above sequence traces. Arrowheads denote altered nucleotides. Lines and arrows indicate positions of mutations in relation to exon D and protein domain E. (G) For the 5 missense mutations (p.R178W, p.D286G, p.R320W, p.R343W, and p.R477Q) conservation across evolution of altered amino acid residues is shown.