Human Molecular Genetics Advance Access originally published online on March 20, 2007
Human Molecular Genetics 2007 16(9):1091-1097; doi:10.1093/hmg/ddm058
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Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis
1 Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC, 41013 Sevilla, Spain, 2 Clinical Genetics, Department of Pediatrics, 3 Department of Pediatrics, University of Padova, 35128 Padova, Italy and 4 Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
* To whom correspondence should be addressed at: Clinical Genetics, Department of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. Tel: +39 0498213513; Fax: +39 0498211425; Email: leonardo.salviati{at}unipd.it
Received January 24, 2007; Revised February 28, 2007; Accepted March 10, 2007
Coenzyme Q10 (CoQ10) deficiency has been associated with an increasing number of clinical phenotypes that respond to CoQ10 supplementation. In two siblings with encephalomyopathy, nephropathy and severe CoQ10 deficiency, a homozygous mutation was identified in the CoQ10 biosynthesis gene COQ2, encoding polyprenyl-pHB transferase. To confirm the pathogenicity of this mutation, we have demonstrated that human wild-type, but not mutant COQ2, functionally complements COQ2 defective yeast. In addition, an equivalent mutation introduced in the yeast COQ2 gene also decreases both CoQ6 concentration and growth in respiratory-chain dependent medium. Polyprenyl-pHB transferase activity was 33–45% of controls in COQ2 mutant fibroblasts. CoQ-dependent mitochondrial complexes activities were restored in deficient fibroblasts by CoQ10 supplementation, and growth rate was restored in these cells by either CoQ10 or uridine supplementation. This work is the first direct demonstration of the pathogenicity of a COQ2 mutation involved in human disease, and establishes yeast as a useful model to study human CoQ10 deficiency. Moreover, we demonstrate that CoQ10 deficiency in addition to the bioenergetics defect also impairs de novo pyrimidine synthesis, which may contribute to the pathogenesis of the disease.
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