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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.

SUBMITTER: Heeringa SF

PROVIDER: S-EPMC3083770 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

Heeringa Saskia F SF Chernin Gil G Chaki Moumita M Zhou Weibin W Sloan Alexis J AJ Ji Ziming Z Xie Letian X LX Salviati Leonardo L Hurd Toby W TW Vega-Warner Virginia V Killen Paul D PD Raphael Yehoash Y Ashraf Shazia S Ovunc Bugsu B Schoeb Dominik S DS McLaughlin Heather M HM Airik Rannar R Vlangos Christopher N CN Gbadegesin Rasheed R Hinkes Bernward B Saisawat Pawaree P Trevisson Eva E Doimo Mara M Casarin Alberto A Pertegato Vanessa V Giorgi Gianpietro G Prokisch Holger H Rötig Agnès A Nürnberg Gudrun G Becker Christian C Wang Su S Ozaltin Fatih F Topaloglu Rezan R Bakkaloglu Aysin A Bakkaloglu Sevcan A SA Müller Dominik D Beissert Antje A Mir Sevgi S Berdeli Afig A Varpizen Seza S Zenker Martin M Matejas Verena V Santos-Ocaña Carlos C Navas Placido P Kusakabe Takehiro T Kispert Andreas A Akman Sema S Soliman Neveen A NA Krick Stefanie S Mundel Peter P Reiser Jochen J Nürnberg Peter P Clarke Catherine F CF Wiggins Roger C RC Faul Christian C Hildebrandt Friedhelm F

The Journal of clinical investigation 20110411 5

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 SRN ...[more]

PMID: 21540551

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Project description:Harboyan syndrome is a degenerative corneal disorder defined as congenital hereditary endothelial dystrophy (CHED) accompanied by progressive, postlingual sensorineural hearing loss. To date, 24 cases from 11 families of various origin (Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan, Dominican) have been reported. More than 50% of the reported cases have been associated with parental consanguinity. The ocular manifestations in Harboyan syndrome include diffuse bilateral corneal edema occurring with severe corneal clouding, blurred vision, visual loss and nystagmus. They are apparent at birth or within the neonatal period and are indistinguishable from those characteristic of the autosomal recessive CHED (CHED2). Hearing deficit in Harboyan is slowly progressive and typically found in patients 10-25 years old. There are no reported cases with prelinglual deafness, however, a significant hearing loss in children as young as 4 years old has been detected by audiometry, suggesting that hearing may be affected earlier, even at birth. Harboyan syndrome is caused by mutations in the SLC4A11 gene located at the CHED2 locus on chromosome 20p13-p12, indicating that CHED2 and Harboyan syndrome are allelic disorders. A total of 62 different SLC4A11 mutations have been reported in 98 families (92 CHED2 and 6 Harboyan). All reported cases have been consistent with autosomal recessive transmission. Diagnosis is based on clinical criteria, detailed ophthalmological assessment and audiometry. A molecular confirmation of the clinical diagnosis is feasible. A variety of genetic, metabolic, developmental and acquired diseases presenting with clouding of the cornea should be considered in the differential diagnosis (Peters anomaly, sclerocornea, limbal dermoids, congenital glaucoma). Audiometry must be performed to differentiate Harboyan syndrome from CHED2. Autosomal recessive types of CHED (CHED2 and Harboyan syndrome) should carefully be distinguished from the less severe autosomal dominant type CHED1. The ocular abnormalities in patients with Harboyan syndrome may be treated with topical hyperosmolar solutions. However, corneal transplantation (penetrating keratoplasty) represents definitive treatment. Corneal transplantation produces a substantial visual gain and has a relatively good surgical prognosis. Audiometric monitoring should be offered to all patients with CHED2. Hearing aids may be necessary in adolescence.

Dataset Information

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

Publications

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

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