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

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.

SUBMITTER: Heeringa SF 

PROVIDER: S-EPMC3083770 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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

Heeringa Saskia F SF   Chernin Gil G   Chaki Moumita M   Zhou Weibin W   Sloan Alexis J AJ   Ji Ziming Z   Xie Letian X LX   Salviati Leonardo L   Hurd Toby W TW   Vega-Warner Virginia V   Killen Paul D PD   Raphael Yehoash Y   Ashraf Shazia S   Ovunc Bugsu B   Schoeb Dominik S DS   McLaughlin Heather M HM   Airik Rannar R   Vlangos Christopher N CN   Gbadegesin Rasheed R   Hinkes Bernward B   Saisawat Pawaree P   Trevisson Eva E   Doimo Mara M   Casarin Alberto A   Pertegato Vanessa V   Giorgi Gianpietro G   Prokisch Holger H   Rötig Agnès A   Nürnberg Gudrun G   Becker Christian C   Wang Su S   Ozaltin Fatih F   Topaloglu Rezan R   Bakkaloglu Aysin A   Bakkaloglu Sevcan A SA   Müller Dominik D   Beissert Antje A   Mir Sevgi S   Berdeli Afig A   Varpizen Seza S   Zenker Martin M   Matejas Verena V   Santos-Ocaña Carlos C   Navas Placido P   Kusakabe Takehiro T   Kispert Andreas A   Akman Sema S   Soliman Neveen A NA   Krick Stefanie S   Mundel Peter P   Reiser Jochen J   Nürnberg Peter P   Clarke Catherine F CF   Wiggins Roger C RC   Faul Christian C   Hildebrandt Friedhelm F  

The Journal of clinical investigation 20110411 5

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 SRN  ...[more]