The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene
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AuthorLuna-Sánchez, Marta; Díaz-Casado, Elena; Barca, Emanuele; Tejada, Miguel Ángel; Montilla-García, Ángeles; Cobos, Enrique Javier; Escames Rosa, Germaine; Acuña Castroviejo, Darío; Quinzii, Catarina M.; López, Luis Carlos
CoQ multiprotein complexCoq9Mitochondrial myopathyMouse modelNonsense-mediated mRNA decayGeneticsGene therapyMetabolism
Luna-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). [http://hdl.handle.net/10481/36532]
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.
Primary 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.