COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

TLDR

Steroid‑resistant nephrotic syndrome is a common cause of end‑stage renal failure, and although several single‑gene causes have been identified, many pathogenic genes remain unknown and the disease is largely treatment‑refractory. We identified six pathogenic COQ6 mutations in 13 patients from seven families, linking early‑onset steroid‑resistant nephrotic syndrome and sensorineural deafness to defective coenzyme Q10 biosynthesis, and demonstrated that CoQ10 supplementation partially rescues podocyte apoptosis in cellular and zebrafish models, indicating a treatable oto‑renal disorder.

Abstract

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 Q10 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 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 SRNS and hearing loss can be molecularly identified and potentially treated.