The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene Luna-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 complex Coq9 Mitochondrial myopathy Mouse model Nonsense-mediated mRNA decay Genetics Gene therapy Metabolism 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. 2015-06-03T09:19:14Z 2015-06-03T09:19:14Z 2015 info:eu-repo/semantics/article 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] 1757-4676 1757-4684 http://hdl.handle.net/10481/36532 10.15252/emmm.201404632 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ info:eu-repo/semantics/openAccess Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Wiley-Blackwell