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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)
Verlagsversion Volltext DOI PMC
Open Access Gold
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Coenzyme Q(10) Deficiency ; Collapsing Glomerulopathy ; Saccharomyces-cerevisiae ; Ubiquinone Deficiency ; Cerebellar-ataxia ; Kidney-diseases ; Coq2 ; Nephropathy ; Nephrocytes ; Ciliopathy
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 123, Heft: 12, Seiten: 5179-5189 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Investigation
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
PubMed ID 24270420
DOI 10.1172/JCI69000
WOS ID WOS:000327826100024
Scopus ID 84890038202
Erfassungsdatum 2014-01-09
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