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Closed Access item Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis

Authors:López-Martín, José M.
Salviati, Leonardo
Trevisson, Eva
Montini, Giovanni
DiMauro, Salvatore
Quinzii, Catarina
Hirano, Michio
Rodríguez-Hernández, Ángeles
Cordero, Mario D.
Sánchez-Alcázar, José Antonio
Santos-Ocaña, Carlos
Navas, Plácido
Keywords:Alkyl and aryl transferase, Amino acid sequence, Cell division, Coenzymes, Energy metabolism, Enzyme activation, Fibroblasts, Mitochondria, Pyrimidines, Saccharomyces cerevisiae, Ubiquinone, Uridine
Issue Date:20-Mar-2007
Publisher:Oxford University Press
Citation:Human Molecular Genetics 16(9): 1091-1097 (2007)
Abstract:Coenzyme Q(10) (CoQ(10)) deficiency has been associated with an increasing number of clinical phenotypes that respond to CoQ(10) supplementation. In two siblings with encephalomyopathy, nephropathy and severe CoQ(10) deficiency, a homozygous mutation was identified in the CoQ(10) 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 CoQ(6) 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 CoQ(10) supplementation, and growth rate was restored in these cells by either CoQ(10) 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 CoQ(10) deficiency. Moreover, we demonstrate that CoQ(10) deficiency in addition to the bioenergetics defect also impairs de novo pyrimidine synthesis, which may contribute to the pathogenesis of the disease.
Description:7 páginas, 4 figuras, 3 tablas.
Publisher version (URL):http://dx.doi.org/10.1093/hmg/ddm058
E-ISSNmetadata.dc.identifier.doi = DOI:1460-2083
Appears in Collections:(CABD) Artículos

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