COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

WOS: 000290246800035

PubMed ID: 21540551

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q(10) biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q(10) treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q(10)-related forms of SRNS and hearing loss can be molecularly identified and potentially treated.

NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK076683, DK086542, GM45952, DK46073, P30 DK081943]; KMD Foundation; Thrasher Research Fund; German Research Foundation (DFG)German Research Foundation (DFG) [SFB 423, TP B19]; German Federal Ministry of Science and Education through the National Genome Research Network; European CommunityEuropean Community (EC) [EUNEFRON 201590]; Fondazione CARIPARO Telethon ItalyFondazione Telethon [GGP09207]; Spanish FIS [PI080500]; Neph-Cure Foundation; American Heart AssociationAmerican Heart Association

We thank the affected individuals and their families for participation. We thank Corina Nailescu for contribution of clinical data. This research was supported by grants from the NIH to F. Hildebrandt (DK076683 and DK086542), C.F. Clarke (GM45952), and R.C. Wiggins (DK46073 and P30 DK081943) and by a grant from the KMD Foundation and the Thrasher Research Fund to F. Hildebrandt. F. Hildebrandt is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Frederick G.L. Huetwell Professor. H. Prokisch was supported by the Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215), by the German Network for Mitochondria] Disorders (mitoNET 01GM0862 and 01GM0867), and by Systems Biology of Metabotypes (SysMBo 0315494A): The work was further supported by a grant from the German Research Foundation (DFG, SFB 423, TP B19) to M. Zenker, by the German Federal Ministry of Science and Education through the National Genome Research Network to G. Nurnberg and P. Nurnberg, by the European Community FP7 program (EUNEFRON 201590) to D. Muller, by Fondazione CARIPARO Telethon Italy (GGP09207) to L. Salviati, by a Spanish FIS grant (PI080500) to P. Navas, and by the Young Investigator Career Development Grant from the Neph-Cure Foundation and the National Scientist Development Grant from the American Heart Association to C. Paul.