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Ashraf, S.* ; Gee, H.Y.* ; Woerner, S.* ; Xie, L.T.X.* ; Vega-Warner, V.* ; Lovric, S.* ; Fang, H.* ; Song, X.W.* ; Cattran, D.C.* ; Avila-Casado, C.* ; Paterson, A.D.* ; Nitschke, P.* ; Bole-Feysot, C.* ; Cochat, P.* ; Esteve-Rudd, J.* ; Haberberger, B. ; Allen, S.J.* ; Zhou, W.B.* ; Airik, R.* ; Otto, E.A.* ; Barua, M.* ; Al-Hamed, M.H.* ; Kari, J.A.* ; Evans, J.* ; Bierzynska, A.* ; Saleem, M.A.* ; Bockenhauer, D.* ; Kleta, R.* ; El Desoky, S.* ; Hacihamdioglu, D.O.* ; Gok, F.* ; Washburn, J.* ; Wiggins, R.C.* ; Choi, M.* ; Lifton, R.P.* ; Levy, S.* ; Han, Z.G.* ; Salviati, L.* ; Prokisch, H. ; Williams, D.S.* ; Pollak, M.* ; Clarke, C.F.* ; Pei, Y.* ; Antignac, C.* ; Hildebrandt, F.*

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

J. Clin. Invest. 123, 5179-5189 (2013)
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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 Q(10) (CoQ(10)) biosynthesis. Mutations in ADCK4 resulted in reduced COQ(10). 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 CoQ(10) 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 CoQ(10) addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ(10) treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ(10) biosynthesis may be treatable with CoQ(10).
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Coenzyme Q(10) Deficiency ; Collapsing Glomerulopathy ; Saccharomyces-cerevisiae ; Ubiquinone Deficiency ; Cerebellar-ataxia ; Kidney-diseases ; Coq2 ; Nephropathy ; Nephrocytes ; Ciliopathy
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 123, Issue: 12, Pages: 5179-5189 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)