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

Lookup NU author(s): Mohamed Al-Hamed


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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).

Publication metadata

Author(s): Ashraf S, Gee HY, Woerner S, Xie LTX, Vega-Warner V, Lovric S, Fang H, Song XW, Cattran DC, Avila-Casado C, Paterson AD, Nitschke P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou WB, Airik R, Otto EA, Barua M, Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA, Bockenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z, Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, Hildebrandt F

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2013

Volume: 123

Issue: 12

Pages: 5179-5189

Print publication date: 02/12/2013

Online publication date: 25/11/2013

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI69000


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Funder referenceFunder name
Deanship of Scientific Research; King Abdulaziz University, Jeddah
Fondazione CARIPARO
National Center for Research Resources
Kidney Foundation of Canada and Nephcure Canada
Kids Kidney Research and Garfield Weston Foundation
King Abdul-Aziz University
National Research Foundation
Nephcure Foundation
2012-305608European Community's 7th Framework program
0919609National Science Foundation
2012R1A6A3A03040212Ministry of Education, Science and Technology
AHA-0630178NAmerican Heart Association
ANR-08GENOPAT-017-01Association Francaise contre les Myopathies
DMP 2010-11-20-386Fondation pour la Recherche Medicale
GM 007185Ruth L. Kirschstein NIH Service Award
mitoNET 01GM1113CGerman Network of mitochondrial disorders