COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness
Saskia F. Heeringa, … , Christian Faul, Friedhelm Hildebrandt
Saskia F. Heeringa, … , Christian Faul, Friedhelm Hildebrandt
Published April 11, 2011
Citation Information: J Clin Invest. 2011;121(5):2013-2024. https://doi.org/10.1172/JCI45693.
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Research Article Nephrology

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.

Authors

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 ϖzen, 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

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Figure 1

Positional cloning of COQ6 mutations in individuals with NS and SND.

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Positional cloning of COQ6 mutations in individuals with NS and SND. ...
(A) lod score profile across the human genome in affected children from 14 consanguineous kindred with SRNS. Parametric heterogeneity lod (HLOD) scores are plotted against human chromosomal mapping positions, concatenated from p-ter (left) to q-ter (right). (B) Within the SRNS2 locus, haplotypes from 250k SNP analysis are shown for 3 of the 7 families with homozygosity at the SRNS2 locus. Alleles are colored light green (AA), dark green (BB), and red (AB). (C) The 32 genes within the SRNS2 locus; 3 genes preferentially expressed in kidney podocytes are underlined. Mutations were found in COQ6. Transcriptional direction is indicated by < or >. (D) COQ6 extends over 13.2 kb and contains 12 exons (boxes). (E) Exon structure of COQ6 cDNA. Arrows indicate relative positions of mutations (see G). Positions of peptides for antibody generation are shown in yellow. (F) Domain structure of COQ6 protein. Extent of the monooxygenase domain is shown in relation to encoding exon position (E). (G) 6 different COQ6 mutations in 7 families with SRNS. Family number and amino acid change (see Table 1) are given above sequence traces. Arrows denote positions of mutations in relation to exons and protein domains. For the 2 missense mutations, G255R and A363D, full conservation across evolution of altered amino acid residues is illustrated.