title: The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene.
abstract: 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 (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB 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-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 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.
authors: Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Marta
authors: M
authors: Luna-Sánchez
authors: Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Elena
authors: E
authors: Díaz-Casado
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors: Emanuele
authors: E
authors: Barca
authors: Departamento de Farmacología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Neurociencias, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Miguel Ángel
authors: MÁ
authors: Tejada
authors: Departamento de Farmacología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Neurociencias, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Ángeles
authors: Á
authors: Montilla-García
authors: Departamento de Farmacología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Neurociencias, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Enrique Javier
authors: EJ
authors: Cobos
authors: Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Germaine
authors: G
authors: Escames
authors: Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
authors: Dario
authors: D
authors: Acuña-Castroviejo
authors: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors: Catarina M
authors: CM
authors: Quinzii
authors: Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain luisca@ugr.es.
authors: Luis Carlos
authors: LC
authors: López
mesh_terms: D000818:Animals; D001259:Ataxia / Q000473:pathology*; D004195:Disease Models, Animal; D014644:Genetic Variation; D005838:Genotype; D062385:Hydroxybenzoates / Q000008:administration & dosage / Q000633:toxicity; D008322:Mammals; D051379:Mice; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000473:pathology*; D018908:Muscle Weakness / Q000473:pathology*; D020125:Mutation, Missense; D014451:Ubiquinone / Q000172:deficiency* / Q000235:genetics
chemical_list: D062385:Hydroxybenzoates; D014451:Ubiquinone; C017704:beta-resorcylic acid; C030571:ubiquinone 9
keywords: CoQ multiprotein complex; Coq9; mitochondrial myopathy; mouse model; nonsense‐mediated mRNA decay