The clinical heterogeneity of coenzyme Q 10 deficiency results from genotypic differences in the Coq9 gene

Abstract

Primary coenzyme Q 10 (CoQ 10 ) 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 ( Coq9 Q95X and Coq9 R239X ), and their responses to 2,4‐dihydroxybenzoic acid (2,4‐di HB ). Coq9 R239X mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4‐di HB increasing CoQ levels. In contrast, Coq9 Q95X 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‐di HB . We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ 9 protein in Coq9 R239X 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. image Two different premature terminations in the COQ 9 protein uniquely affect the expression levels of components of the multiprotein complex for CoQ biosynthesis, establishing for the first time a genotype/clinical phenotype relationship with therapeutic consequences. The first mouse model of mild mitochondrial myopathy due to CoQ deficiency was generated and characterized ( Coq9 Q95X ). The clinical phenotypes of CoQ deficiency observed in two mouse models ( Coq9 Q95X and Coq9 R239X ) are caused by genotypic difference in the Coq9 gene and were influenced by the efficiency of nonsense‐mediated mRNA decay. CoQ multiprotein complex for CoQ biosynthesis was destabilized by the presence of a truncated protein in Coq9 R239X mice, leading to a severe CoQ deficiency and clinical phenotype. Whether a bypass therapy aimed at increasing CoQ biosynthesis is successful depends on CoQ biosynthetic proteins levels.