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dc.contributor.authorLuna-Sánchez, Marta
dc.contributor.authorDíaz-Casado, Elena
dc.contributor.authorBarca, Emanuele
dc.contributor.authorTejada, Miguel Ángel
dc.contributor.authorMontilla-García, Ángeles
dc.contributor.authorCobos, Enrique Javier
dc.contributor.authorEscames Rosa, Germaine 
dc.contributor.authorAcuña Castroviejo, Darío 
dc.contributor.authorQuinzii, Catarina M.
dc.contributor.authorLópez, Luis Carlos
dc.identifier.citationLuna-Sánchez, M.; et al. The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene. Embo Molecular Medicine, 7(5): 670-687 (2015). []es_ES
dc.description.abstractPrimary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype–phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9Q95X and Coq9R239X), and their responses to 2,4‐dihydroxybenzoic acid (2,4‐diHB). Coq9R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4‐diHB increasing CoQ levels. In contrast, Coq9Q95X mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late‐onset mild mitochondrial myopathy, which does not respond to 2,4‐diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9R239X mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype–phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.es_ES
dc.description.sponsorshipThis work was supported by grants from the Marie Curie International Reintegration Grant Programme (COQMITMEL-266691 to LCL) within the Seventh European Community Framework Programme, from Ministerio de Economía y Competitividad, Spain (SAF2009-08315 and SAF2013-47761-R to LCL), from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (P10-CTS-6133 to LCL), and from the ‘CEIBioTic’ (20F12/1 to LCL). MLS is a predoctral fellow from the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía. LCL is supported by the ‘Ramón y Cajal’ National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643). MAT is supported by a predoctoral grant from the University of Granada. EJC is supported by the Research Program of the University of Granada. CMQ is supported by NICHD Grants 5K23 HDO65871-05 and P01 HD080642-01, and by a MDA grant. The proteomic analysis was performed in the CSIC/UAB Proteomics Facility of IIBB-CSIC that belongs to ProteoRed, PRB2-ISCIII, supported by Grant PT13/0001.es_ES
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 3.0 Licensees_ES
dc.subjectCoQ multiprotein complexes_ES
dc.subjectMitochondrial myopathyes_ES
dc.subjectMouse modeles_ES
dc.subjectNonsense-mediated mRNA decayes_ES
dc.subjectGenetics es_ES
dc.subjectGene therapy es_ES
dc.subjectMetabolism es_ES
dc.titleThe clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 genees_ES

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