COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

Saskia F. Heeringa, Gil Chernin, Moumita Chaki, Weibin Zhou, Alexis J. Sloan, Ziming Ji, Letian X. Xie, Leonardo Salviati, Toby W. Hurd, Virginia Vega-Warner, Paul D. Killen, Yehoash Raphael, Shazia Ashraf, Bugsu Ovunc, Dominik S. Schoeb, Heather M. McLaughlin, Rannar Airik, Christopher N. Vlangos, Rasheed Gbadegesin, Bernward HinkesPawaree Saisawat, Eva Trevisson, Mara Doimo, Alberto Casarin, Vanessa Pertegato, Gianpietro Giorgi, Holger Prokisch, Agnès Rötig, Gudrun Nürnberg, Christian Becker, Su Wang, Fatih Ozaltin, Rezan Topaloglu, Aysin Bakkaloglu, Sevcan A. Bakkaloglu, Dominik Müller, Antje Beissert, Sevgi Mir, Afig Berdeli, Seza Özen, Martin Zenker, Verena Matejas, Carlos Santos-Ocaña, Placido Navas, Takehiro Kusakabe, Andreas Kispert, Sema Akman, Neveen A. Soliman, Stefanie Krick, Peter Mundel, Jochen Reiser, Peter Nürnberg, Catherine F. Clarke, Roger C. Wiggins, Christian Faul, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

217 Citations (Scopus)

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 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 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.

Original languageEnglish (US)
Pages (from-to)2013-2024
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number5
DOIs
StatePublished - May 2 2011

Fingerprint

Nephrotic Syndrome
Deafness
coenzyme Q10
Steroids
Mutation
Podocytes
Stria Vascularis
Kidney
Ubiquinone
Golgi Apparatus
Zebrafish
Inner Ear
Mixed Function Oxygenases
Hearing Loss
Genes
Chronic Kidney Failure
Embryonic Structures
Yeasts
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Heeringa, S. F., Chernin, G., Chaki, M., Zhou, W., Sloan, A. J., Ji, Z., ... Hildebrandt, F. (2011). COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. Journal of Clinical Investigation, 121(5), 2013-2024. https://doi.org/10.1172/JCI45693

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. / 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; Rötig, Agnès; Nürnberg, Gudrun; Becker, Christian; Wang, Su; Ozaltin, Fatih; Topaloglu, Rezan; Bakkaloglu, Aysin; Bakkaloglu, Sevcan A.; Müller, Dominik; Beissert, Antje; Mir, Sevgi; Berdeli, Afig; Özen, Seza; Zenker, Martin; Matejas, Verena; Santos-Ocaña, Carlos; Navas, Placido; Kusakabe, Takehiro; Kispert, Andreas; Akman, Sema; Soliman, Neveen A.; Krick, Stefanie; Mundel, Peter; Reiser, Jochen; Nürnberg, Peter; Clarke, Catherine F.; Wiggins, Roger C.; Faul, Christian; Hildebrandt, Friedhelm.

In: Journal of Clinical Investigation, Vol. 121, No. 5, 02.05.2011, p. 2013-2024.

Research output: Contribution to journalArticle

Heeringa, SF, Chernin, G, Chaki, M, Zhou, W, Sloan, AJ, Ji, Z, Xie, LX, Salviati, L, Hurd, TW, Vega-Warner, V, Killen, PD, Raphael, Y, Ashraf, S, Ovunc, B, Schoeb, DS, McLaughlin, HM, Airik, R, Vlangos, CN, Gbadegesin, R, Hinkes, B, Saisawat, P, Trevisson, E, Doimo, M, Casarin, A, Pertegato, V, Giorgi, G, Prokisch, H, Rötig, A, Nürnberg, G, Becker, C, Wang, S, Ozaltin, F, Topaloglu, R, Bakkaloglu, A, Bakkaloglu, SA, Müller, D, Beissert, A, Mir, S, Berdeli, A, Özen, S, Zenker, M, Matejas, V, Santos-Ocaña, C, Navas, P, Kusakabe, T, Kispert, A, Akman, S, Soliman, NA, Krick, S, Mundel, P, Reiser, J, Nürnberg, P, Clarke, CF, Wiggins, RC, Faul, C & Hildebrandt, F 2011, 'COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness', Journal of Clinical Investigation, vol. 121, no. 5, pp. 2013-2024. https://doi.org/10.1172/JCI45693
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 ; Rötig, Agnès ; Nürnberg, Gudrun ; Becker, Christian ; Wang, Su ; Ozaltin, Fatih ; Topaloglu, Rezan ; Bakkaloglu, Aysin ; Bakkaloglu, Sevcan A. ; Müller, Dominik ; Beissert, Antje ; Mir, Sevgi ; Berdeli, Afig ; Özen, Seza ; Zenker, Martin ; Matejas, Verena ; Santos-Ocaña, Carlos ; Navas, Placido ; Kusakabe, Takehiro ; Kispert, Andreas ; Akman, Sema ; Soliman, Neveen A. ; Krick, Stefanie ; Mundel, Peter ; Reiser, Jochen ; Nürnberg, Peter ; Clarke, Catherine F. ; Wiggins, Roger C. ; Faul, Christian ; Hildebrandt, Friedhelm. / COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 5. pp. 2013-2024.
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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 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 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.",
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AU - Heeringa, Saskia F.

AU - Chernin, Gil

AU - Chaki, Moumita

AU - Zhou, Weibin

AU - Sloan, Alexis J.

AU - Ji, Ziming

AU - Xie, Letian X.

AU - Salviati, Leonardo

AU - Hurd, Toby W.

AU - Vega-Warner, Virginia

AU - Killen, Paul D.

AU - Raphael, Yehoash

AU - Ashraf, Shazia

AU - Ovunc, Bugsu

AU - Schoeb, Dominik S.

AU - McLaughlin, Heather M.

AU - Airik, Rannar

AU - Vlangos, Christopher N.

AU - Gbadegesin, Rasheed

AU - Hinkes, Bernward

AU - Saisawat, Pawaree

AU - Trevisson, Eva

AU - Doimo, Mara

AU - Casarin, Alberto

AU - Pertegato, Vanessa

AU - Giorgi, Gianpietro

AU - Prokisch, Holger

AU - Rötig, Agnès

AU - Nürnberg, Gudrun

AU - Becker, Christian

AU - Wang, Su

AU - Ozaltin, Fatih

AU - Topaloglu, Rezan

AU - Bakkaloglu, Aysin

AU - Bakkaloglu, Sevcan A.

AU - Müller, Dominik

AU - Beissert, Antje

AU - Mir, Sevgi

AU - Berdeli, Afig

AU - Özen, Seza

AU - Zenker, Martin

AU - Matejas, Verena

AU - Santos-Ocaña, Carlos

AU - Navas, Placido

AU - Kusakabe, Takehiro

AU - Kispert, Andreas

AU - Akman, Sema

AU - Soliman, Neveen A.

AU - Krick, Stefanie

AU - Mundel, Peter

AU - Reiser, Jochen

AU - Nürnberg, Peter

AU - Clarke, Catherine F.

AU - Wiggins, Roger C.

AU - Faul, Christian

AU - Hildebrandt, Friedhelm

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N2 - 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 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.

AB - 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 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.

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