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 Hinkes; Pawaree 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 Varpizen; 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

doi:10.1172/JCI45693

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 Varpizen, 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 journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2013-24
Number of pages	12
Journal	Journal of Clinical Investigation
Volume	121
Issue number	5
DOIs	https://doi.org/10.1172/JCI45693
Publication status	Published - May 2011

Keywords

Animals
COS Cells
Cercopithecus aethiops
Child
Child, Preschool
HeLa Cells
Hearing Loss, Sensorineural
Homozygote
Humans
Infant
Infant, Newborn
Intracellular Signaling Peptides and Proteins
Kidney Glomerulus
Laminin
Membrane Proteins
Mutation
Nephrotic Syndrome
Phenotype
Podocytes
Rats
Ubiquinone
WT1 Proteins
Zebrafish

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10.1172/JCI45693

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness
© 2011, American Society for Clinical Investigation
Final published version, 1.78 MB

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Heeringa, S. F., Chernin, G., Chaki, M., Zhou, W., Sloan, A. J., Ji, Z., Xie, L. X., Salviati, L., Hurd, T. W., Vega-Warner, V., Killen, P. D., Raphael, Y., Ashraf, S., Ovunc, B., Schoeb, D. S., McLaughlin, H. M., Airik, R., Vlangos, C. N., Gbadegesin, R., ... Hildebrandt, F. (2011). COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. Journal of Clinical Investigation, 121(5), 2013-24. https://doi.org/10.1172/JCI45693

@article{3cd81c63ec974509bf4f627127794b8a,

title = "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.",

keywords = "Animals, COS Cells, Cercopithecus aethiops, Child, Child, Preschool, HeLa Cells, Hearing Loss, Sensorineural, Homozygote, Humans, Infant, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Kidney Glomerulus, Laminin, Membrane Proteins, Mutation, Nephrotic Syndrome, Phenotype, Podocytes, Rats, Ubiquinone, WT1 Proteins, Zebrafish",

author = "Heeringa, {Saskia F} and Gil Chernin and Moumita Chaki and Weibin Zhou and Sloan, {Alexis J} and Ziming Ji and Xie, {Letian X} and Leonardo Salviati and Hurd, {Toby W} and Virginia Vega-Warner and Killen, {Paul D} and Yehoash Raphael and Shazia Ashraf and Bugsu Ovunc and Schoeb, {Dominik S} and McLaughlin, {Heather M} and Rannar Airik and Vlangos, {Christopher N} and Rasheed Gbadegesin and Bernward Hinkes and Pawaree Saisawat and Eva Trevisson and Mara Doimo and Alberto Casarin and Vanessa Pertegato and Gianpietro Giorgi and Holger Prokisch and Agn{\`e}s R{\"o}tig and Gudrun N{\"u}rnberg and Christian Becker and Su Wang and Fatih Ozaltin and Rezan Topaloglu and Aysin Bakkaloglu and Bakkaloglu, {Sevcan A} and Dominik M{\"u}ller and Antje Beissert and Sevgi Mir and Afig Berdeli and Seza Varpizen and Martin Zenker and Verena Matejas and Carlos Santos-Oca{\~n}a and Placido Navas and Takehiro Kusakabe and Andreas Kispert and Sema Akman and Soliman, {Neveen A} and Stefanie Krick and Peter Mundel and Jochen Reiser and Peter N{\"u}rnberg and Clarke, {Catherine F} and Wiggins, {Roger C} and Christian Faul and Friedhelm Hildebrandt",

year = "2011",

month = may,

doi = "10.1172/JCI45693",

language = "English",

volume = "121",

pages = "2013--24",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "5",

}

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, Varpizen, 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. 2013-24. https://doi.org/10.1172/JCI45693

TY - JOUR

T1 - COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

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 - Varpizen, 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

PY - 2011/5

Y1 - 2011/5

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 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.

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 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.

KW - Animals

KW - COS Cells

KW - Cercopithecus aethiops

KW - Child

KW - Child, Preschool

KW - HeLa Cells

KW - Hearing Loss, Sensorineural

KW - Homozygote

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Intracellular Signaling Peptides and Proteins

KW - Kidney Glomerulus

KW - Laminin

KW - Membrane Proteins

KW - Mutation

KW - Nephrotic Syndrome

KW - Phenotype

KW - Podocytes

KW - Rats

KW - Ubiquinone

KW - WT1 Proteins

KW - Zebrafish

U2 - 10.1172/JCI45693

DO - 10.1172/JCI45693

M3 - Article

C2 - 21540551

VL - 121

SP - 2013

EP - 2024

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

Abstract

Keywords

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