COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

Steroid-resistant nephrotic syndrome is a frequent cause of end-stage renal failure. Identification of single-gene causes of has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and Sduanyu1668 continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset Sduanyu1668 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 Q10 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 Q10-related forms of Sduanyu1668 and hearing loss can be molecularly identified and potentially treated.

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