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.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Saskia F
authors.initials: SF
authors.lastname: Heeringa
authors.forename: Gil
authors.initials: G
authors.lastname: Chernin
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Sloan
authors.forename: Ziming
authors.initials: Z
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authors.forename: Letian X
authors.initials: LX
authors.lastname: Xie
authors.forename: Leonardo
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authors.lastname: Salviati
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authors.lastname: Hurd
authors.forename: Virginia
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authors.forename: Dominik S
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authors.lastname: McLaughlin
authors.forename: Rannar
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authors.forename: Christopher N
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authors.lastname: Vlangos
authors.forename: Rasheed
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authors.lastname: Gbadegesin
authors.forename: Bernward
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authors.lastname: Hinkes
authors.forename: Pawaree
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authors.lastname: Saisawat
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Mara
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authors.lastname: Doimo
authors.forename: Alberto
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authors.lastname: Casarin
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pertegato
authors.forename: Gianpietro
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authors.lastname: Giorgi
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Gudrun
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authors.lastname: Nürnberg
authors.forename: Christian
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authors.lastname: Becker
authors.forename: Su
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authors.lastname: Wang
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.forename: Rezan
authors.initials: R
authors.lastname: Topaloglu
authors.forename: Aysin
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Sevcan A
authors.initials: SA
authors.lastname: Bakkaloglu
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.forename: Antje
authors.initials: A
authors.lastname: Beissert
authors.forename: Sevgi
authors.initials: S
authors.lastname: Mir
authors.forename: Afig
authors.initials: A
authors.lastname: Berdeli
authors.forename: Seza
authors.initials: S
authors.lastname: Varpizen
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Verena
authors.initials: V
authors.lastname: Matejas
authors.forename: Carlos
authors.initials: C
authors.lastname: Santos-Ocaña
authors.forename: Placido
authors.initials: P
authors.lastname: Navas
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Sema
authors.initials: S
authors.lastname: Akman
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krick
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Clarke
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
authors.forename: Christian
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authors.lastname: Faul
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000150:complications / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007678:Kidney Glomerulus / Q000378:metabolism; D007797:Laminin / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009404:Nephrotic Syndrome / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism; D051381:Rats; D014451:Ubiquinone / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics; D015027:Zebrafish
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D008565:Membrane Proteins; C407223:NPHS2 protein; D025721:WT1 Proteins; C113267:nephrin; C032165:ubiquinone 6; C058783:laminin beta2; D014451:Ubiquinone