Coq6 Mutations In Human Patients Produce Nephrotic Syndrome With Sensorineural Deafness
Tarih
2011Yazar
Heeringa, Saskia F.
Chernin, Gil
Chaki, Moumita
Zhou, Weibin
Sloan, Alexis J.
Ji, Ziming
Xie, Letian X.
Salviati, Leonardo
Hurd, Toby W.
Vega-Warner, Virginia
Killen, Paul D.
Raphael, Yehoash
Ashraf, Shazia
Ovunc, Bugsu
Schoeb, Dominik S.
McLaughlin, Heather M.
Airik, Rannar
Vlangos, Christopher N.
Gbadegesin, Rasheed
Hinkes, Bernward
Saisawat, Pawaree
Trevisson, Eva
Doimo, Mara
Casarin, Alberto
Pertegato, Vanessa
Giorgi, Gianpietro
Prokisch, Holger
Roetig, Agnes
Nuernberg, Gudrun
Becker, Christian
Wang, Su
Ozaltin, Fatih
Topaloglu, Rezan
Bakkaloglu, Aysin
Bakkaloglu, Sevcan A.
Mueller, Dominik
Beissert, Antje
Mir, Sevgi
Berdeli, Afig
Ozen, Seza
Zenker, Martin
Matejas, Verena
Santos-Ocana, Carlos
Navas, Placido
Kusakabe, Takehiro
Kispert, Andreas
Akman, Sema
Soliman, Neveen A.
Krick, Stefanie
Mundel, Peter
Reiser, Jochen
Nuernberg, Peter
Clarke, Catherine F.
Wiggins, Roger C.
Faul, Christian
Hildebrandt, Friedhelm
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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.